







































 

_____________________________________________________________________________________________________ 
 
*Corresponding author: E-mail: arvindkumarshukla@pusan.ac.kr; arvindkumarshuklapnu@gmail.com 
 
Cite as: Shukla, Sandhya, Arvind Kumar Shukla, Navin Ray, Adarsha Mahendra Upadhyay, Giovanna Mirone, and Raj Kumar 
Mongre. 2024. “Long-Lasting Response of Human Circulating T-Follicular Helper Cells (cTfh) To Post SARS-CoV-2 MRNA 
Immunization”. Asian Journal of Immunology 7 (1):228-46. https://journalaji.com/index.php/AJI/article/view/147. 
 

 
 

Asian Journal of Immunology 
 
Volume 7, Issue 1, Page 228-246, 2024; Article no.AJI.125387 
 

 
 

 

 

Long-lasting Response of Human 
Circulating T-follicular Helper Cells 
(cTfh) To Post SARS-CoV-2 mRNA 

Immunization 
 

Sandhya Shukla a, Arvind Kumar Shukla b*, Navin Ray c, 
Adarsha Mahendra Upadhyay d, Giovanna Mirone e  

and Raj Kumar Mongre f 
 

a Department of Pharmacology, Bharati Vidyapeeth Deemed University Medical College,  
Pune-411043, India. 

b School of Biomedical Convergence Engineering, Pusan National University, Yangsan-50612,  
South Korea. 

c Laboratory of Mucosal Exposome and Biomodulation, Department of Integrative Biomedical 
Sciences, Pusan National University, Yangsan-50612, South Korea. 

d Department of Gastrointestinal Surgery, School of Overseas Education, Guizhou Medical University, 
Guiyang, Guizhou-550025, China. 

e Department of Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, University of 
Campania Luigi Vanvitelli; via Vivaldi 43, Caserta-81100, Italy. 

 f Department of Surgery, Boston Children's Hospital, Harvard Medical School, Harvard University, 300 
Longwood Ave, Boston, MA 02115, USA. 

 

Authors’ contributions  
 

This work was carried out in collaboration among all authors. All authors read and approved the final 
manuscript. 

 

Article Information 
 

DOI: https://doi.org/10.9734/aji/2024/v7i1147  
 

Open Peer Review History: 
This journal follows the Advanced Open Peer Review policy. Identity of the Reviewers, Editor(s) and additional Reviewers, peer 

review comments, different versions of the manuscript, comments of the editors, etc. are available here: 
https://www.sdiarticle5.com/review-history/125387  

 

 
 

Received: 04/09/2024 
Accepted: 06/11/2024 
Published: 13/11/2024 

 

Review Article 

https://doi.org/10.9734/aji/2024/v7i1147
https://www.sdiarticle5.com/review-history/125387


 
 
 
 

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ABSTRACT 
 

The ongoing COVID-19 pandemic underscores the urgent need for effective vaccination strategies 
to mitigate disease burden. The development of neutralizing antibodies is a critical indicator of host 
defence mechanisms against life-threatening infectious diseases, such as those caused by SARS-
CoV-2. Understanding the fundamental biological mechanisms and substantiality of these 
antibodies' production is essential for developing effective vaccines, particularly in the face of 
emerging variants. Circulating T follicular helper (cTfh) cells, which have emerged as significant 
predictors of neutralizing antibody levels, are of utmost importance in shaping long-term immunity 
following vaccination. We emphasize the pivotal role of cTfh cells in shaping long-term immunity, 
providing reassurance about the effectiveness of vaccines. In this study, we elucidate the functions 
of cTfh cells and their lymphoid counterparts during immune responses to SARS-CoV-2, particularly 
in the context of spike protein vaccination. We explore the phenotypic diversity of cTfh cells and 
their potential as biomarkers for development of SARS-CoV-2 vaccine efficacy with long-lasting 
immunity. The identification of specific cTfh subgroups may inform strategies for enhancing vaccine 
responses, especially concerning new SARS-CoV-2 variant-specific vaccines. Future research 
directions will focus on harnessing the predictive capabilities of cTfh cells to optimize vaccine 
development and improve immunological outcomes against evolving SARS-CoV-2 strains. 
 

 
Keywords: T follicular helper cells; SARS-CoV-2; COVID-19; CD4+ T cells. 
 

ABBREVIATIONS 
 
PD-1 : Programmed cell death protein-1  
CCR7 : CC-chemokine receptor 7  
CXCR3 : CXC-chemokine receptor 3  
CCR6 : CXC-chemokine receptor 6  
CXCR5 : CXC-chemokine receptor 5  
ICOS : Inducible T cell co-stimulator  
Tfh : Follicular helper T cell  
cTfh : Circulating Tfh cell 

 
1. INTRODUCTION  
 
The emergence of SARS-CoV-2, the virus 
responsible for the COVID-19 pandemic, has 
prompted an unprecedented global effort to 
develop effective vaccines. Among the most 
promising vaccine platforms are those based on 
mRNA technology, which offers several 
advantages, including rapid development, 
scalability, and the potential for modification [1]. 
As vaccination campaigns have progressed 
worldwide, understanding the immune responses 
elicited by these vaccines has become 
paramount. Investigating the dynamics of 
circulating T-follicular helper cells (cTfh), a 
subset of CD4+ T cells crucial for B cell 
activation and antibody production is essential for 
evaluating vaccine efficacy and durability [2]. The 
role of cTfh cells in orchestrating humoral 
immune responses has been extensively studied 
in the context of various infections and 
vaccinations. These specialized T cells live within 
secondary lymphoid organs, interacting with B 

cells to promote germinal center reactions, 
affinity maturation, and the generation of long-
lived plasma cells and memory B cells. 
Importantly, cTfh cells play a central role in 
shaping the size and quality of antibody 
responses, which are critical for protection 
against viral infections [3].  
 

In the context of SARS-CoV-2 mRNA 
vaccination, understanding the kinetics and 
durability of cTfh cell responses is particularly 
interesting. mRNA vaccines, such as those 
developed by Pfizer-BioNTech and Moderna, 
encode the viral spike (S) protein, which 
mediates viral entry into host cells. Upon 
vaccination, antigen-presenting cells process and 
present S protein fragments to T cells, leading to 
the activation and differentiation of cTfh cells. 
These cTfh cells then migrate to B cell follicles 
within lymphoid organs, where they provide help 
to B cells undergoing somatic hypermutation and 
class-switch recombination, ultimately promoting 
the production of high-affinity antibodies against 
SARS-CoV-2 [4,5]. Initial studies investigating 
cTfh responses to SARS-CoV-2 mRNA 
vaccination have offered valuable insights into 
the kinetics and size of these responses. For 
instance, several reports have shown robust 
expansion of cTfh cells following vaccination, 
peaking within weeks after the first dose and 
declining gradually thereafter. Significantly, the 
frequency and functionality of cTfh cells have 
been correlated with the size and persistence of 
antibody responses, suggesting their crucial role 
in vaccine-induced immunity. Furthermore, 



 
 
 
 

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emerging evidence suggests that cTfh cell 
responses to SARS-CoV-2 mRNA vaccination 
may show heterogeneity across individuals, 
influenced by factors such as age, sex, and 
immunological history. Understanding the 
determinants of cTfh cell dynamics and their 
impact on vaccine efficacy and durability is 
essential for optimizing vaccination strategies 
and informing public health policies [6,7].  
 
The immunoglobulin family consists of five 
classes: IgM, IgA, IgE, IgG, and IgD. Each              
class has its characteristics and function [8]. 
Primary immunoglobulin M (IgM) is expressed              
in the early stages of B cell maturation and                   
is linked to primary immunological responses. 
IgA protects mucosal surfaces from bacteria, 
viruses, and toxins. IgE plays a role in                   
allergic reactions, hypersensitivity reactions, and 
the defense against parasitic infections. IgG, 
which is functionally divided into four subclasses 
(IgG1, IgG2, IgG3, and IgG4), is essential for 

both the effectiveness of vaccinations and 
antiviral defences. IgD has a short serum half-life 
and is present at low concentrations, and its 
specific function is currently unknown [8,9]     
(Fig. 1). 
 
This review aims to comprehensively evaluate 
the current literature on human cTfh cell 
responses to SARS-CoV-2 mRNA vaccination, 
focusing on the kinetics, size, durability, and 
correlates of protection. We will discuss key 
findings from clinical studies and preclinical 
models, highlighting gaps in knowledge and 
areas for future research. Additionally, we will 
explore the implications of cTfh cell responses 
for vaccine development, including strategies to 
enhance immunogenicity and durability. By 
elucidating the role of cTfh cells in vaccine-
induced immunity against SARS-CoV-2, this 
review aims to contribute to the ongoing efforts to 
control the COVID-19 pandemic and prepare for 
future outbreaks. 

  

 
 

Fig. 1. Shows how several Tfh cell subsets contribute to the production of immunoglobulins 
with several functions. Pre-Tfh (pTfh) cells can differentiate into Tfh1, Tfh2, or Tfh17 

phenotypes in response to different microenvironmental signals from different healthy or 
pathological conditions. Because each subgroup of Tfh cells has specific functional 
characteristics, they can coordinate B cell development towards producing various 

immunoglobulin types essential for various immunological responses. Reproduced/adapted 
with permission [9]. 



 
 
 
 

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2. EMERGING ROLE OF Tfh CELLS FOR 
NOVEL SARS-CoV-2 VACCINE 
DEVELOPMENT 

 

According to the findings, CD4 T-cell responses 
to SARS-CoV-2 were 80–100% on antigen-
specific T-cell responses in patients treated after 
SARS-CoV-2 infection, with most research 
mainly concentrating on spike (S) protein [10-13]. 
According to other investigations, T-cells have 
also been found to target the nucleocapsid (N) 
and membrane (M) proteins [14]. Developing 
effective SARS-CoV-2 vaccines has been 
recognized as a significant step toward 
preventing the COVID-19 pandemic. Neutralizing 
antibodies (nAb) are a reliable indicator of 
immunity against infection and immunization in 
rhesus macaques [15,16]. Neutralizing 
antibodies have been identified as the critical 
factor of vaccination effectiveness in phase I/II 
trials of the Pfizer and Moderna vaccines and 
many other candidate vaccines [17-20]. Whereas 
the Pfizer vaccine was showcased to induce CD4 
and CD8 T-cell responses in trial participants, 
and vaccine-induced CD4 T-cell responses 
correlated with antibody levels [21], with our 
knowledge of both the precise immune factors 
that are associated with protection as well as the 
durability of this immune function is still lacking. 
Furthermore, the factors that trigger the 
production of nAb in the presence of 
spontaneous SARS-CoV-2 infection are crucial 
to investigate, especially in the situation of new 
viral variations that may be different mechanisms 
of pathogenic infections developing [22,23]. 
Several studies have found a significant increase 
in activation and exhaustion markers on T cells in 
moderate and severe SARS-CoV-2 illnesses [24-
27]. Whereas studying lymphoid tissues directly 
within patients is challenging, circulating T 
follicular cells (cTfh), also known as T follicular 
helper cells (Tfh), act as a helpful alternative for 
investigating Tfh responses in germinal centers. 
However, significant debate was over the 
optimum method to recognize these cells. It was 
widely agreed that they express CXCR5, a lymph 
node homing receptor, but several researchers 
also utilized PD1 expression in combination with 
CXCR5 to identify cTfh [28-30]. Even though the 
number of CXCR5+ PD1+ CD4 T cells in the 
bloodstream is generally low, these cells are 
closely related to Tfh in lymphoid tissue [31] and 
enhance adaptive immunity defences [32,33]. In 
the circumstances of infection and Vaccination 
against numerous diseases, antigen-specific 
cTfh is associated significantly with neutralizing 
antibodies [29,34-38]. Even if cTfh responses 

were not discussed in the specific situation of 
SARS-CoV or MERS-CoV infection, CD4 T-cell 
responses were demonstrated to be crucial in 
regulating SARS-CoV throughout mouse models 
[39], as well as Tfh frequencies in draining lymph 
nodes associated with neutralizing antibodies 
throughout the latest research on the MERS-CoV 
vaccine in mice [40].  

 
Much research about SARS-CoV-2-specific T 
follicular helper cellular transformation by 
different signaling pathways exists. Thevarajan et 
al. were among the first to publish SARS-CoV-2 
cTfh frequencies, discovering that overall cTfh 
frequencies are increased during acute infection 
[41]. Several studies have discovered a link 
between total CD4 T-cell frequencies and 
antibody levels [42,43]. Another research report 
enhanced gene expression of CXCR5 and ICOS, 
two Tfh markers, among SARS-CoV-2-specific 
CD4 T-cells but did not confirm cTfh effects [44]. 
However, Kaneko et al. discovered that BCL6-
expression throughout germinal centre Tfh has 
been lost within thoracic lymph nodes of 
deceased donors with COVID-19, implying that 
Tfh response initiation may be inhibited in 
serious SARS-CoV-2 infection [45]. The initiation 
of antigen-specific Tfh responses, especially in 
asymptomatic patients with COVID-19, is still a 
mystery. In their study, Juno et al. investigated 
circulating Tfh, recognized as CD45RA CXCR5+ 
CD4 T cells, in the blood of SARS-CoV-2 
infected people. They discovered a link between 
S protein-specific cTfh and nAb, indicating that 
effective Tfh responses were produced in 
moderate SARS-CoV-2 infection [46]. 
Unfortunately, these findings leave other aspects 
unresolved, particularly once those responses 
change throughout the recovery period. Even 
though this research work provided a preliminary 
look at antigen specific Tfh responses, which 
included PD1, a conventional Tfh marker, within 
the research frame, PD1 expression needed 
more utilized to characterize the Tfh population 
and was not published. Furthermore, Ox40 and 
CD25 were utilized as initiation markers to detect 
antigen-specific responses that have already 
been reported and demonstrated to contain a 
significant fraction of regulating T-cells [47]. A 
current study has the durability of S protein-
specific CD4 T-cell responses after recovery [48]. 
The authors have considered only the incidence 
of circulating Tfh (ICOS+ CXCR5+ CD4 T cells) 
each month and three months after the 
symptoms started. While they found responses 
higher than backgrounds after three months, 
there was no change throughout the duration.  



 
 
 
 

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Additional analysis of CD4 T-cell and cTfh 
responses during the recovery period might help 
to determine how much these responses change 
and evolve. Several recent studies [49,50] have 
investigated cTfh groups up to 6 months after the 
onset of symptoms. (Investigations used too 
much). Unfortunately, this ongoing research 
failed due to the failure to examine connections 
among antigen-specific cTfh and SARS-CoV-2-
specific antibodies. In addition, these types of 
research were predominantly concerned with S 
protein-specific effects. For example, 
Infrastructural assistance emerges in HIV 
infection during Vaccination, when CD4 T-cell 
responses towards internal structural proteins 
correspond with neutralizing antibodies against 
the outer envelope protein [51,52], emphasizing 
the necessity of studying cTfh responses from 
across the SARS-CoV-2 proteome. Boppana et 
al. report on SARS-CoV-2-specific CD4 T-cell 
activation to membrane (M), nucleocapsid (N), 
and spike (S) proteins in 26 recovered patients 
who were studied in real-time. They studied 
antigen-specific cTfh (CXCR5+ PD1+ CD4 T 
cells) and found connections among antigen-
specific cTfh responses across all protein 
specificities with antibody neutralization during 
the first convalescent visit. They observed that 
the M protein-specific cTfh responses increase 
during Check Up 1 towards Check Up 2 (>5% 
activation of the total cTfh population). These 
responses did not correspond to antibody 
neutralization at only the second recovered              
visit and more than thirty days after illness  
onset. Such findings are always the earliest              
to investigate the speed of cTfh responses 
following SARS-CoV-2 infection and the link 
between neutralizing antibodies and cTfh 
sensitivities to SARS-CoV-2 M and N proteins. 
This research also suggests that cTfh 
development may be postponed in SARS-CoV-2 
infections [53]. 
 

3. PHENOTYPES AND FUNCTIONS OF 
FOLLICULAR HELPER T CELLS (Tfh) 
OF SARS-CoV-2 INFECTION 

 

Follicular Helper T Cells (Tfh) cells are used as a 
functional indicator; they can promote B cells by 
increasing antibody production, long-lived 
plasma cells, and memory B cells [54,55]. Tfh 
cell markers, which typically include chemokine 
receptor CXCR5, transcription factor Bcl-6, PD-1, 
CD40 ligand (CD40L), and ICOS in humans and 
mice, are essential for identifying Tfh cells with 
their various subgroups not only in lymphoid 
tissue but also in circulation [56-59]. Additionally, 

the phenotypes of Tfh cells were linked to distinct 
phases of immunological responses [60,61]. 
Within secondary lymphoid organs, naïve CD4+ T 
cells develop into Tfh cells through CXCR5 
overexpression and CCR7 reduced expression, 
which is controlled by antigen-specific 
conventional dendritic cells (DCs) and monocyte-
derived DCs [58,62,63]. Tfh cells migrate into 
CXC-chemokine ligand 13 (CXCL13)-enriched B 
lymphoid follicles inside the germinal centre (GC) 
due to enhanced CXCR5 and reduced CCR7 
[58,64]. In Human and mouse GCs, the unique 
transcription factor Bcl-6 was exclusively 
expressed among Tfh cells and was highly 
expressed within CXCR5hiCCR7low/-Tfh cells 
[64-67]. A cytokine, Interleukin-21 (IL-21), is 
firmly and selectively released only Tfh cells, 
which increases Tfh cell proliferation and 
enhances B cell differentiation and antibody 
production, which is typical for Tfh cells [68-72]. 
In both mice as well as humans, ICOS reduction 
greatly lowers GC reactions but also Tfh cells, 
indicating that ICOS expression in Tfh cells is 
required during Tfh cell differentiation and 
maintenance, GC production, and B cell 
differentiation, including antibody responses [73-
75]–66]. As an essential effector molecule, ICOS 
could also promote IL-21 release within Tfh cells 
[75-77]. Tfh cell development and activation 
could be considerably enhanced by increased 
PD-1 expression [78-80]. Tfh cells were usually 
classified as having three phenotypes: precursor-
Tfh (Pre-Tfh) cells, canonical GC Tfh cells with 
PD-1++ and ICOS++Bcl-6+ CCR7- CXCR5++CD4+ T 
cells characterized as PD-1+ ICOS+ Bcl-
6lowCCR7lowCXCR5+ CD4+ T cells, and memory 
Tfh cells similar to Pre-Tfh cells in lymphoid 
tissue [33,81,82]. Tfh cells regulate B cell 
differentiation, becoming memory B cells as well 
as plasma cells in GC, and even select for high-
affinity antibody production to form long-term 
innate immunity [83-86]. 
 
Circulating Tfh (cTfh) cells in the blood typically 
have two different phenotypes: central memory 
Tfh cells (PD-1- ICOS-CCR7highBCL-6- CXCR5+ 
CD4+ T cells) and effector memory Tfh cells (PD-
1+ICOS+CCR7lowBCL-6- CXCR5+ CD4+ T cells) 
[61,87,88]. Similarly, cTfh cells were categorized 
under three subgroups depending on the 
expression of either CXCR3 as well as CCR6: 
Tfh1 (CXCR3+ CCR6-), Tfh2 (CXCR3- CCR6- ), 
Tfh17 (CXCR3- CCR6+), and Tfh1/17 (CXCR3+ 
CCR6+) cells that contain the hallmark gene 
transcription factors and cytokines comprising 
Th1 (T-bet as well as IFN-g), Th2 (GATA3, IL-4, 
IL-5, and IL-13), with Th17 (RORgt, IL-17, and 



 
 
 
 

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233 

 

IL-22) cells [61,87,89]. cTfh2 with cTfh17 cells 
potentially stimulates B cell differentiation with 
antibody production and regulates (Ig-antibodies) 
isotype changing. Although cTfh1 cells are not 
commonly considered B cell helpers, ICOS+ PD-
1highCCR7lowcTfh1 cells control B cell 
differentiation and trigger antibody responses 
[89-95]. Depending on the expression of ICOS, 
PD-1, and CCR7, as well as CXCR3 and CCR6, 
these findings show functionally different cTfh 
cell subgroups. Furthermore, emerging unique 
subgroups distinguish among Th1, Th2, and 
Th17 cells while sharing some fundamental 
properties. Tfh-like cells were also recognized in 
non-lymphoid tissues, such as arthritis synovium 
and skin, but also salivary glands of patients, that 
also widely express low expression of CXCR5 
and Bcl-6 and high PD-1, ICOS, OX40, and IL-
21, especially in comparison to Tfh cells in 
secondary lymphoid organs, that also express 
tissue-specific chemokine receptors, such as 
CCR2, CCR5, CX3C-chemokine receptor 1 
(CX3CR1) and CXCR4 [82,96-100]. Tfh13 cells, 
a unique Tfh cell subgroup that produces and 
secretes IL-4 with IL-13, have been newly                
found to be essential for IgE production in               
both human and mouse allergies, and they 
exhibit the signaling molecules Bcl-6 and GATA3 
[101-103].  
 
According to current research, specific 
phenotypes for Tfh cells are required during B 
cell differentiation and high-affinity antibody 
production (Table 1). More importantly, follicular 
regulatory T (Tfr) cells are a subpopulation of 
Foxp3+ Treg cells inside the GC, launched 
through Foxp3+/-precursors and not just from Tfh 
cells [104-107]. Tfr cells express Tfh cell markers 
such as CXCR5, Bcl-6, PD-1, and ICOS and 
Treg cell molecules such as CD25, Foxp3, 
Blimp-1, and CTLA-4 [108-111]. Tfr cells, like 
Treg cells, play a significant role in 
immunosuppression that is greater than that of 
Tfh cells. Tfh cells can restrict GC responses and 
reduce Tfh and B cell activation inside GCs via 
inhibitory molecules such as CTLA-4, PD-1, and 
IL-10, as well as TGF-b production. Tfh/Tfr cell 
equilibrium was required to regulate 
immunological homeostasis and modulate innate 
immunity [92,96,111-114]. 
 

4. MECHANISM OF SARS-CoV-2 mRNA 
 
“Presently, the emerging SARS-CoV-2 infectious 
outbreak is causing a significant challenge for 

global healthcare across the globe. Innate 
immunity is required for neutralizing antibodies 
and is essential in vaccination reactions against 
pathogenic virus infections, such as SARS-CoV-
2, which have been linked to Tfh cell 
differentiation and function” [55,115-120] (Fig. 2). 
Tfh cells have been studied for their role in 
regulating the eradication of SARS-CoV-2 
infections and developing novel vaccines.  
 
Much research showed a high frequency of cTfh 
cells with the CXCR5+ICOS+PD-1+ phenotype. In 
a patient with especially non-recovering COVID-
19 patient, specific plasma SARS-CoV-2-binding 
IgM and IgG antibodies increased exponentially 
approximately 20 days after infection, with a 
combination of enhanced specific plasma SARS-
CoV-2-binding IgM as well as IgG antibodies 
[41]. Single-cell investigation showed that 
individuals with active COVID-19 infection had 
higher frequencies of cTfh cells and a large 
percentage with specific anti-SARS-CoV-2 
antibodies, such as IgA and IgG [121]. “In 
recovered COVID-19 patients, the percentages 
of Spike (S)-specific cTfh cells 
(CD3+CD4+CD45RA–CXCR5+) are continuously 
produced after S-peptide activation and show a 
significant phenotypic inclination toward the 
aCCR6+CXCR3-cTfh17 cell phenotype. Another 
study discovered that significantly enlarged 
CXCR3+cTfh1 cells were associated with such a 
solid neutralizing immunological response to 
influenza vaccination and live attenuated yellow 
fever immunization” [37,122]. 
 
The latest research found that increasing 
numbers of CCR7lowPD-1+ cTfh-effector 
memory (em), cTfh1 but instead cTfh2 cells, and 
also high IL-1b and TNF-a, are found in 
CXCR5+CD45RACD25-CD4+T cells, and 
therefore, cTfh1 cells were related to increased 
SARS-CoV-2-specific IgG/IgM antibodies. While 
CCR7highPD-1-cTfh-central memory (cm) and 
cTfh17 cells within CXCR5+CD45RACD25-
CD4+T cells were reduced in recovered patients 
compared to healthy patients, cTfr cells within 
Treg cells were increased. The frequency of high 
cTfh-em, low cTfh-cm, and cTfr cells was also 
associated with disease severity [43]. These 
findings suggest that cTfh cell morphological 
characteristics can produce significant 
neutralized antibodies toward SARS-CoV-2 in 
COVID-19-recovered patients, which will help 
develop antibody-based treatments and vaccines 
for COVID-19. 

 
 



 
 
 
 

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Table 1. Phenotypes of Tfh cell subsets in blood and lymphoid tissue 
 

Location Cell subsets Phenotypic markers Ref. 

 

Lymphoid tissues 

Pre-Tfh cells PD-1+ ICOS+ CCR7lowBcl-6lowBlimp-1- CXCR5+  

 

 

 

[62,87,88] 

 

GC Tfh cells PD-1++ICOS++CCR7- Bcl-6+ Blimp-1- CXCR5++ 

Memory Tfh cells PD-1+ ICOS+ CCR7lowBcl-6lowBlimp-1- CXCR5+ 

 

 

 

 

Blood 

cTfh1/17 cells IFN-g + IL-17A+ Bcl-6- Blimp-1- CXCR5+                     (or)                                                                                                          
CXCR3+ CCR6+ Bcl-6- Blimp-1- CXCR5+ 

cTfh17 cells IL-17A+ Bcl-6- Blimp-1- CXCR5+                     (or)                                                                                                          
CXCR3- CCR6+ Bcl-6- Blimp-1- CXCR5+ 

cTfh2 cells IL-4+ Bcl-6- Blimp-1- CXCR5+                                                       (or)                                                       
CXCR3- CCR6- Bcl-6- Blimp-1- CXCR5+ 

cTfh1 cells IFN-g + Bcl-6- Blimp-1- CXCR5+                                                   (or)                                                                                                                  
PD-1+ ICOS+ CCR7lowCXCR3+ CCR6- Bcl-6- Blimp-1- CXCR5+ 

Effector memory Tfh cells CD40L+ /PD-1+ /ICOS+ CCR7lowBcl-6- Blimp-1- CXCR5+ 

Central memory Tfh cells PD-1- ICOS-CCR7highBcl-6- Blimp-1- CXCR5+ 

cTfh13 cells IL-13hiIL-4hiIL-5hiIL-21lowBcl-6+ GATA3+ CXCR5+ [101-103] 
† PD-1, programmed cell death protein-1; CCR7, CC-chemokine receptor 7; CXCR3, CXC-chemokine receptor 3; CCR6, CXC-chemokine receptor 6; CXCR5, CXC-chemokine receptor 

5; ICOS, inducible T cell co-stimulator 

 
  



 
 
 
 

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Table 2. Tfh cell responses in various vaccine candidates of SARS-CoV-2 

Vaccine candidates Phenotypes Function Antibody 
isotypes 

Ref. 

mRNA vaccines 

BNT162b2 mRNA vaccine AIM+ CXCR5+ CD45RA-CD3+ cTfh cells expansion, AIM cells 
include CD69+ OX40+ or CD69+ CD40L+ (or) CD69+ 4-1BB+ 

(or) OX40+ 4-1BB+ (or) CD40L+ 4-1BB+ (or) CD40L+ OX40+ 

Positively correlate with anti-spike-
specific IgA and IgG titers. 

 
IgA, IgG 

 
 
 
 
[124] 
 
 

RBD mRNA (receptor binding 
domain, RBD) 

B220-CD4+ CD44hiCD62L-CXCR5+ Bcl-6+ Tfh cells, B220- 
CD4+ CD44hiCXCR5+ PD-1hi IL-21+ Tfh cells, B220- CD4+ 
CD44hiCXCR5+ Bcl-6+ ICOS+ Tfh cells, B220- CD4+ 
CD44hiCXCR5+ PD-1hi IFN-g + Tfh cells notable expansion 
 

Elicit potent SARS-CoV-2-specific 
GC B responses and induce robust 
and specific antibody responses, 
including neutralizing antibodies. 

 
gG1, IgG2a, 
IgG2b, 

full SΔ furin mRNA B220- CD4+ CD44hiCD62L-CXCR5+ Bcl-6+ Tfh cells, B220-
CD4+ CD44hiCXCR5+ PD-1hi IL-21+ Tfh cells, B220-CD4+ 

CD44hiCXCR5+ Bcl-6+ ICOS+ Tfh cells B220-CD4+ 

CD44hiCXCR5+ PD-1hi 

Elicit potent SARS-CoV-2-specific 
GC B responses and induce robust 
and specific antibody responses, 
including neutralizing antibodies. 

 
IgG1, IgG2a, 
IgG2b, 

 
[130] 

mRNA-1273 IL-21+ CXCR5+ PD−1+ ICOS+ Tfh cells expansion. Induce robust and specific antibody 
responses, including neutralizing 
antibodies. 

IgA, IgG  
[123] 

Protein vaccines 

StriFK-FH002C PD-1+ CXCR5+ CD4+ Tfh cells expansion Induce specific antibody 
responses, including neutralizing 
antibodies. 

IgG, IgG1, IgG2a, 
IgG2b 

 
[129] 

Spike (S) and receptor binding 
domain (RBD) protein subunit 
vaccine 

CXCR5++BCL-6+ CD4+ CD3+ B220-Tfh cells expansion Induce specific antibody 
responses, including neutralizing 
antibodies. 

 
IgG 

 
[125] 
 

NVX-CoV2373 CXCR5+ PD-1+ CD4+ Tfh cells expansion Induce specific antibody 
responses, including neutralizing 
antibodies. 

 
IgG 

 
[4] 

rRBD-AddaVax B220-CD4+ CD44hiCD62L-CXCR5+ Bcl-6+ Tfh cells, B220-
CD4+ CD44hiCXCR5+ PD-1hi IL-21+ Tfh cells B220-CD4+ 
CD44hiCXCR5+ PD-1hi IL-4+ Tfh cells slight expansion 

Delay in eliciting potent SARS-
CoV-2-specific GC B responses 
induces robust and specific 
antibody responses, including 
neutralizing antibodies. 

 
IgG1 
 

 
[130] 
 

† Tfh, follicular helper T cell; cTfh, circulating Tfh cell 

 
 



 
 
 
 

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236 

 

 
 

Fig. 2. The involvement of signaling pathways in controlling Tfh cell differentiation and function in SARS-CoV-2 infection with vaccines. When 
exposed to SARS-CoV-2 or viral antigens, naive CD4+ T cells were activated through APCs (DCs), which are triggered against antigen-specific Pre-
Tfh cells by the association of MHC-II molecules between DCs with cognate TCR on CD4+ T cells, and the expression of costimulatory molecules 
with cytokine production, pre-Tfh cells associate with active B cells at the T-B boundary in the follicular zone, wherein they develop into diverse 
Tfh cell subtypes that move to the GC, wherein Tfh cells stimulate B cell differentiation and specific antibody production. Reproduced/adapted 

with permission [131] 



 
 
 
 

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237 

 

 
 

Fig. 3. Lymphoid and circulating TFH responses in COVID-19. SARS-CoV-2 antigen in the 
lymph nodes activates antigen-specific B cells and TFH cells. Their interaction leads to the 
initiation of the germinal centre reaction. This results in the development of memory B cells 

with increased somatic hypermutation (SHM) and increased affinity, as well as long-lived 
plasma cells that traffic to the bone marrow and provide a long-term source of neutralizing 

antibodies. A population of short-lived antibody-secreting cells (ASCs) appears in the 
circulation and provides a rare source of neutralizing antibodies. Concurrently, a population of 
activated (CD38+, PD-1+, ICOS+) cTfh cells appears in the circulation. This population contains 

antigen-specific cTfh cells (not depicted). Although memory B cells and ASCs are primarily 
located in lymphoid tissues, they are typically measured in blood samples, which correlate 

with activated cTfh cells. Activated cTfh cells also correlate with the development of 
neutralizing antibodies. These cTfh cells are a potential biomarker of TFH activity in lymphoid 
tissues. However, it remains to be determined if this population of cTfh cells are predictive of 

long-term neutralizing antibodies or the development of long-lived plasma cells and the 
prolonged evolution of the MBC pool. Reproduced/adapted with permission [135]. 

 

Rapid advances have been made in designing 
and developing SARS-CoV-2 vaccines, such as 
inactivated DNA, mRNA, and specific SARS-
CoV-2 proteins [123]. The mRNA-1273 vaccine 
can effectively activate Th1 and interleukin-21 
expressing CXCR5+PD1+ICOS+Tfh cellular 
responses as well as trigger powerful SARS-

CoV-2 neutralizing potential, providing quick 
protection against SARS-CoV-2 infection in the 
vertical and horizontal airways of Rhesus 
Macaques [4]. In contrast to the SARS-CoV-2 
recombinant SARS-CoV-2 receptor-binding 
domain (rRBD) developed for the AddaVax 
(rRBD-AddaVax) protein vaccine gene, the 



 
 
 
 

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238 

 

SARS-CoV-2 mRNA vaccine gene encodes RBD 
as well as full-length spike protein efficiently to 
prompt SARS-CoV-2-specific GC B and Tfh 
cellular responses, which also enhance specific 
neutralizing antibody responses in inoculated 
mice. Surprisingly, the rRBD-AddaVax 
Vaccination produced a significant proportion of 
IL-4+ Tfh cells [124]. The BNT162b2 mRNA 
vaccine against SARS-CoV-2 produced 
significant AIM+CXCR5+CD45RA-CD3+cTfh cell 
responses in humans. AIM (activation-induced 
marker) cells are including CD69+OX40+ or 
CD69+CD40L+ or CD69+4-1BB+ or OX40+4-1BB+ 
or CD40L+4-1BB+ or CD40L+4-1BB+ or CD40L 
[4]. The above results show that SARS-CoV-2 
mRNA vaccines can help enhance antigen-
specific Tfh cell differentiation and B cell 
responses, as well as the production of 
protective immune responses by producing 
antibodies, making them especially potential for 
eliciting high-quality adaptive immune responses 
to regulate as well as eradicate SARS-CoV-2 
infection. 
 

Moreover, “target protein vaccines such as the 
SARS-CoV-2 subunit vaccine (NVX-CoV2373) 
with both the full-length Spike (S)-protein, StriFK-
FH002C, as well as the Spike (S)/receptor 
binding domain (RBD) protein subunit vaccine 
remarkably stimulate specific cTfh cell but                
also GC B cell responses, leading to high SARS-
CoV-2” [125-127] neutralizing levels of antibodies 
(Table 2). Several human clinical studies show 
that immobilized SARS-CoV-2 vaccinations can 
produce sufficient high neutralizing levels of 
antibodies to decrease                the rate of 
patients developing severe          COVID-19 [127-
129]. Such findings imply that SARS-CoV-2 
vaccinations can boost host immune response, 
increase neutralizing antibody levels, and reduce 
the death rate of critically ill patients. 
 

Meanwhile, in serious COVID-19 patients, the 
absence of GC structures lowers Bcl-6+ Tfh 
cells. Interestingly, SARS-CoV-2-specific Tfh 
cells significantly increased in moderate and 
asymptomatic COVID-19 patients. Vaccines also 
can stimulate Tfh cell differentiation and GC 
production, including defensive antibody 
responses. 
 

5. HUMAN CIRCULATING T FOLLICULAR 
HELPER CELLS (cTfh) RESPONSE 
AGAINST COVID-19 

 

Activated cTfh (PD-1+ICOS+) [41,43,132-134] 
with enhanced expression of CD38 [135] but also 
decreased expression of CCR7 [43] is seen in 

the blood during acute infection. Such activated 
PD-1+ICOS+ cTfh cells appear spontaneously 
throughout the infection but typically decrease 14 
days after symptom onset. As a result, antigen-
specific T cell tests (activation-induced marker 
(AIM) and intracellular cytokine staining) were 
crucial to evaluating SARS-CoV-2-specific cTfh 
responses throughout recovery. These studies 
have also shown that S-specific cTfh cells that 
arise following acute infection [136] remain in 
convalescent patients for at least 6 months [32], 
with a half-life of approximately 129 days [50]. 
 
The link between cTfh frequencies, 
morphological and functional polarization, and 
SARS-CoV-2 serologic responses have been 
investigated. Most of the PD1+ICOS+ cTfh 
populations formed during the acute stage of 
COVID-19 are CXCR3+cTfh1 cells [132,134], 
similar to influenza infection [137]. Moreover, the 
investigation of S-specific cTfh showed a 
completely dominant population of CXCR3–

CCR6+ cells [46,49,136]. Remarkably, the 
fraction of CXCR3–CCR6+ S-specific cTfh cells 
during late convalescence (6 months) is more 
significant than that in initial convalescence (1–2 
months) or even during the acute stage [49,136]. 
Despite the presence of CXCR3CCR6+ cTfh17 
cells, antigen-specific cTfh cells from COVID-19 
patients routinely release IFN and IL-21, even 
when IL-17 is not present, according to multiple 
independent studies [46,48-50,133,136,137]. 
The development of effective neutralizing 
antibody responses has been associated with a 
phenotypic polarization of cTfh. Furthermore, 
high levels of serum spike binding and 
neutralizing antibodies were strongly associated 
with CXCR3+ cTfh1 cells. This was true not only 
for the overall ICOS+PD-1+ cTfh1 populations 
(which corresponds to ASC responses and 
plasma CXCL13) [43,132-134], but also for S-
specific cTfh1 [46]. The activation of cTfh1 cells 
in acute COVID-19 significantly corresponds with 
both the confirmatory testing and antibody 
production of RBD-specific IgM antibodies [46]. 
“The association between cTfh2, cTfh17, and 
antibody response, on the other hand, varies 
among cohorts and tests. The discovery of S-
specific cTfh led to the conclusion that the 
occurrence of cTfh2 responses was positively 
correlated with increasing neutralizing levels of 
antibodies, whereas S-specific cTfh17 showed a 
significant negative correlation with neutralizing 
activity” [46]. Overall, ICOS+PD1+ cTfh2/17 cells 
were significantly negatively correlated with 
antibody response in different populations 
[43,46,133,134]. Therefore, the present               



 
 
 
 

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239 

 

findings show that CXCR3+ cTfh1 cells are a 
significant correlate of neutralizing as well as 
overall antibodies towards SARS-CoV-2, but             
the roles of CXCR3–cTfh2 and cTfh17 cells, as 
well as the differences between total ICOS+PD-
1+ and AIM+ cTfh cells, deserve additional 
exploration.  

 
Whereas most research has concentrated on S-
specific cTfh cells, N and M-specific cTfh cells 
were also investigated [53,136,138]. The 
proportion of cTfh cells specific for S, N, and M 
was shown to be favourably linked to increased 
plasma neutralization activity with N-specific IgG 
antibodies [53]. Remarkably, for cTfh cells 
specific towards various SARS-CoV-2 antigens, 
polarisation throughout cTfh1, cTfh2, and cTfh17 
subgroups has been shown to change [138], but 
the relevance of this result is still unknown. A 
possible decrease of TFH cells has also been 
identified in some patients with acute COVID-19. 
In particular, GC-B cells and TFH cells were 
shown to be reduced in lymphoid tissues of a 
subgroup of deceased COVID-19 patients 
[45,53]. “Furthermore, a population with cTfh 
cells expressing cytotoxicity-associated genes, 
including PRF1 and GZMB (encoding perforin 
and granzyme B), was enhanced in hospitalized 
vs. nonhospitalized patients. It was also linked 
with decreased antibody levels to S” [139]. Such 
findings contradict the more significant antibodies 
found in acute COVID-19 [132] because 
decreased TFH function would be predicted to 
decrease antibody levels. Such findings highlight 
the need for more research into the nature and 
function of TFH cells in acute COVID-19 and 
whether they correspond to a specific population 
of patients.  

 
Finally, total stimulation of cTfh cells and 
associated phenotypic polarisation throughout 
COVID-19 are indicators of B-cell reaction 
neutralization (Fig. 3). Furthermore, the 
phenotypic traits of the different cTfh subgroups, 
including their link with GC Tfh activities, must be 
clarified. It is crucial to investigate the                 
potential for cTfh cells as indicators of the 
formation and recall of humoral immunity to 
SARS-CoV-2, particularly in developing variants 
of concern (VOCs) with a higher potential for 
evasion of humoral immunity. It is essential to 
investigate the potential for cTfh cells as 
indicators of the formation and recall of humoral 
immunity to SARS-CoV-2, particularly in 
developing variants of concern (VOCs)                  
with a higher potential for evasion of humoral 
immunity. 

6. HUMAN CIRCULATING T-FOLLICULAR 
HELPER CELLS (cTfh) RESPONSES 
AFTER SARS-CoV-2 VACCINATION 

 
Vaccination with certified COVID-19 vaccines 
produces antibody responses linked to infection 
prevention. Following mRNA vaccination, 
examination of axillary draining lymph nodes 
showed substantial GC responses that were 
maintained for a minimum of 12 weeks following 
booster vaccination [140]. S-specific Tfh cells 
were significantly produced at those sites 
because they were associated with S-specific 
GC B cells [124,141]. According to an evaluation 
of associated lymph nodes and blood samples, 
S-specific cTfh cells show an activated 
phenotype (CD38+HLA-DR+ICOS+) increase 
during the first month before reverting to a 
resting phenotype and then decreasing in 
frequency. Within a minimum of 60 days, the 
frequency of S-specific Tfh cells within lymph 
nodes is majorly consistent [141]. Despite being 
confined to a limited number of donors, our 
results indicate that mRNA vaccines trigger 
significant GC responses, which may highlight 
the vaccine's outstanding immunological 
characteristics. Vaccination of naive (previously 
uninfected) humans produces S-specific cTfh 
cells [142-148] with such a CXCR3+ phenotype 
[142] as well as the potential to produce IFN, 
although without IL-17A [4]. At a minimum, S-
specific cTFH cell frequency increases 
approximately one month after immunization and 
subsequently decreases, compared with S-
specific TH1 cell frequency, which remains 
constant for a minimum of 6 months [144]. At two 
weeks following Vaccination, the number of S-
specific cTfh cells and S-specific conventional 
CD4+ TH1 cells corresponds to neutralizing 
antibodies against Spike and VOCs and S with 
RBD-specific MBC responses [86]. This suggests 
that cTfh cells serve as indicators again for the 
production of neutralizing antibodies with MBCs 
and subsequent spike vaccination. Vaccinating 
people who have recovered from COVID-19 
usually results in higher S-specific cTfh 
responses versus naïve people [4]. Significantly, 
the number of S-specific cTfh cells among 
recovering patients before Vaccination increases 
significantly post-vaccination, neutralizing 
antibody levels observed in both the ancestor's 
viruses and VOC [4,143]. Therefore, it indicates 
that cTfh cells play a significant function as 
biomarkers of innate immunity after SARS-CoV-2 
vaccination. This will be critical to better 
classifying and correctly understanding lymphoid 
and circulating Tfh cell responses after 



 
 
 
 

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240 

 

 
 

Fig. 4. Circulating TFH subsets as correlates of antibody responses. Flow cytometry 
visualization of cTfh subgroups depending on CXCR3 as well as CCR6 expression and its 

relationship with antibody responses in different configurations. Reproduced/adapted with 
permission [135]. 

 
administration of various newly invented vaccine 
systems, as well as whether/how they differently 
activate such responses, particularly in the 
context of heterologous prime-boost Vaccination. 
 

7. FUTURE PROSPECTIVE OF cTfh-
MEDIATED WITH OTHER THERAPIES 
FOR SARS-CoV-2 INFECTION 

 
The future prospects of cTfh-mediated therapies 
in the context of SARS-CoV-2 infection are 
promising, particularly in light of the remarkable 
adaptability of these cells to emerging variants. 
As our understanding of cTfh cell dynamics 
evolves, it becomes increasingly clear that their 
ability to modulate immune responses could be 
harnessed in conjunction with other therapeutic 
approaches. Integrating cTfh-mediated strategies 
with innovative hormonal therapies may enhance 
vaccine efficacy and promote robust long-term 
immunity. By targeting the plasticity of cTfh cells, 
future interventions could be designed to 
optimize immune responses to current variants 
and potential future mutations of SARS-CoV-2, 
thereby improving clinical outcomes and overall 
public health strategies. 

 
8. CONCLUSION 
 

There are strong indications that the cTfh study 
can provide valuable information on the 
quantitative and qualitative characteristics of 
neutralizing antibodies against SARS-CoV-2 
infection during Vaccination (Fig. 4). This 

evidence suggests that cTfh cells, specifically the 
cTfh1 subgroup, were valuable indicators for 
producing neutralizing antibodies and MBCs 
targeting both wild-type Spike and VOCs. 
However, critical issues exist regarding the 
involvement of CXCR3/CCR6 cTfh subgroups in 
generating neutralizing antibodies or maintaining 
spike-specific cTfh memory. To obtain specific 
results on Tfh's ability to produce significant 
neutralizing antibody responses via Vaccination, 
it will be crucial to understand why only specific 
cTfh subgroups correlate positively to antibody 
levels and how Tfh quality may be modified using 
innovative vaccine platforms. Furthermore, 
whereas the cTfh initiation, as well as the 
frequency of antigen-specific cTfh cells, are 
biomarkers of neutralizing antibodies in the acute 
as well as early phases of COVID-19 infection 
but also Vaccination, it is unknown whether cT 
cells indicate the development of long-lived 
plasma cells or long-term neutralizing antibodies. 
Researchers should start understanding more 
about the duration of GC TFH responses and 
their relationship to cTFH frequencies and 
phenotype as research aims to comprehend the 
immunologic processes underpinning the 
persistent development of the MBC pool [145-
147]. Resolving these concerns is critical to 
realizing their promise of developing efficient 
vaccination approaches. 

 
CONSENT 
 
It is not applicable.  



 
 
 
 

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241 

 

ETHICAL APPROVAL 
 
It is not applicable.  

 
DISCLAIMER (ARTIFICIAL INTELLIGENCE) 

 
Author(s) hereby declares that NO generative AI 
technologies such as Large Language Models 
(ChatGPT, COPILOT, etc.) and text-to-image 
generators have been used during the writing or 
editing of this manuscript.  

 
COMPETING INTERESTS 
 
Authors have declared that no competing 
interests exist. 
 

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