Follicular helper T cells (also known as follicular B helper T cells and abbreviated as T
FH), are
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
-experienced
CD4+ T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s found in the periphery within
B cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
follicles of secondary lymphoid organs such as
lymph nodes
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
,
spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . and
Peyer's patches
Peyer's patches (or aggregated lymphoid nodules) are organized lymphoid follicles, named after the 17th-century Swiss anatomist Johann Conrad Peyer.
* Reprinted as:
* Peyer referred to Peyer's patches as ''plexus'' or ''agmina glandularum'' (c ...
, and are identified by their constitutive expression of the
B cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
follicle homing receptor
CXCR5
C-X-C chemokine receptor type 5 (CXC-R5) also known as CD185 (cluster of differentiation 185) or Burkitt lymphoma receptor 1 (BLR1) is a G protein-coupled seven transmembrane receptor for chemokine CXCL13 (also known as BLC) and belongs to the C ...
. Upon cellular interaction and cross-signaling with their cognate
follicular (Fo B) B cells, T
FH cells trigger the formation and maintenance of
germinal center
Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, prolifera ...
s through the expression of
CD40 ligand (CD40L) and the secretion of
IL-21 and
IL-4. T
FH cells also migrate from T cell zones into these seeded
germinal center
Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, prolifera ...
s, predominantly composed of rapidly dividing
B cells
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
mutating their Ig genes. Within germinal centers, T
FH cells play a critical role in mediating the selection and survival of B cells that go on to differentiate either into long-lived
plasma cell
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substan ...
s capable of producing high affinity antibodies against foreign antigen, or germinal center-dependent
memory B cell
In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescen ...
s capable of quick immune re-activation in the future if ever the same antigen is re-encountered. T
FH cells are also thought to facilitate negative selection of potentially
autoimmune
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". P ...
-causing mutated B cells in the
germinal center
Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, prolifera ...
. However, the biomechanisms by which T
FH cells mediate germinal center
tolerance are yet to be fully understood.
It is possible that T
FH cells might arise as branches in the Th1 and Th2 differentiation pathways but their precise lineage relationship to the other effector CD4
+ T cell subsets is still uncertain. Studies have however shown that T
FH have distinct gene expression profiles, supporting the theory that T
FH are a subset of CD4
+ T cells distinct from
Th-1,
Th-2,
Th-17 or
Tregs.
Biomolecular characterization
The
inducible T-cell co-stimulator (''CD278'' or ''ICOS'') is proven to provide a particularly critical signal for T
FH cells since experimental mice deficient in ICOS are unable to develop any T
FH. Additionally, it has been shown that ICOS induces the secretion of
IL-21 cytokine by activated CD4
+ T cells and that IL-21 plays a crucial role in the development of T
FH cells and
germinal center
Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, prolifera ...
s. Also
Bcl-6 is a transcription factor identified in T
FH cells, but it may have roles that extend beyond this subset, because it has also been implicated in memory
CD8+ T cell development.
In germinal centers, antigen-experienced T
FH cells rapidly upregulate the expression of CD40L, which binds and stimulates the B cell surface receptor CD40. T
FH cell-dependent
paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse ove ...
activation of B cell CD40 results in B cell survival and differentiation, including the induction of AID (
activation-induced (cytidine) deaminase
Activation-induced cytidine deaminase, also known as AICDA, AID and single-stranded DNA cytosine deaminase, is a 24 kDa enzyme which in humans is encoded by the ''AICDA'' gene. It creates mutations in DNA by deamination of cytosine base, which t ...
). AID expression (encoded by the ''AICDA'' gene) causes B cell antibodies to class switch from IgM/IgD to other antibody isotypes and drives
somatic hypermutation
Somatic hypermutation (or SHM) is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (e.g. microbes), as seen during class switching. A major component of the process of affinity maturation, SHM div ...
during clonal proliferation. The switched antibodies acquire better effector functions, and hypermutated antibody shows greater affinity for antigen.
Classes of TFH cells
T
FH cells formed early in the nascent stages of a
germinal center
Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, prolifera ...
reaction are formally called pre-T
FH cells. They are uniquely found predominantly at the border of the T cell zone that merges with the B cell follicles and germinal centers. Pre-T
FH cells are functionally very similar to other T
FH cells in facilitating germinal center B cell reactions however, in addition, they are also capable of driving follicular B cell development adjacent to and outside of germinal centers to produce quickly responsive but non-durable
plasma cell
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substan ...
-driven antibody responses (known as the extrafollicular response).
Those T
FH cells specifically residing within a mature germinal center are sometimes referred to as GC T
FH cells (for Germinal Center T
FH cells) to distinguish them from pre-T
FH cells. There is also a minor sub-class within this population of GC Tfh cells that express the gene ''
Foxp3
FOXP3 ( forkhead box P3), also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of ...
'', encoding for a transcription factor. This small discrete sub-population of cells, called T
FR cells (for T Follicular Regulatory cells), are important in helping to control and limit the magnitude of normal germinal center responses such that they avoid the potential to produce abnormally mutated or self-reactive
autoimmune
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". P ...
-associated antibodies. Therefore, T
FR cells are a uniquely inhibitory influence during a germinal center reaction.
While T
FH cells are found primarily in the secondary lymphoid organs, a small proportion circulate in the blood and are termed "peripheral" T follicular helper cells (pT
FH). These cells can be identified by their expression of
IL-21 upon stimulation.
Medical relevance
Generating lasting immune memory
T
FH cells are considered an indispensable T cell subset in the generation and maintenance of
germinal center
Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, prolifera ...
responses. Therefore, in the absence of T
FH cells, similar to B cell activation by T-cell independent antigens, a quick burst of low affinity plasma cell production is formed but this does not lead to germinal center induction nor permit antibody
affinity maturation
In immunology, affinity maturation is the process by which TFH cell-activated B cells produce antibodies with increased affinity for antigen during the course of an immune response. With repeated exposures to the same antigen, a host will produce ...
or the differentiation of effective
memory B cell
In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescen ...
s which are essential in fortifying the body against subsequent infections. Specifically, germinal center-dependent memory B cells are the drivers of recall antibody production during a secondary immune response. Therefore, the proper activation and development of T
FH cells is central to the efficacy of
immunization
Immunization, or immunisation, is the process by which an individual's immune system becomes fortified against an infectious agent (known as the immunogen).
When this system is exposed to molecules that are foreign to the body, called ''non-sel ...
s and
vaccine
A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifie ...
design for the induction of long-term
immunity
Immunity may refer to:
Medicine
* Immunity (medical), resistance of an organism to infection or disease
* ''Immunity'' (journal), a scientific journal published by Cell Press
Biology
* Immune system
Engineering
* Radiofrequence immunity desc ...
. In a Bangladeshi population study of patients infected with ''Vibrio cholerae'' and healthy human volunteers administered with an existing cholera vaccine, a memory T
FH response specifically against cholera antigen had correlated with further antibody production by B cells.
Controlling age-related immune decline
With normal aging comes a gradual diminishing of the body's immune system. This phenomenon called
immunosenescence
Immunosenescence is the gradual deterioration of the immune system, brought on by natural age advancement. A 2020 review concluded that the adaptive immune system is affected more than the innate immune system. Immunosenescence involves both the ...
is largely due to a decline of T cell function, including the capacity for T
FH cells to properly support
germinal center
Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, prolifera ...
responses. This may be in part due to lower
CD40L
CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells and is a member of the TNF superfamily of molecules. It binds to CD40 on antigen-presenting cells (APC), which leads to many effects dependin ...
levels on the cell surface of T
FH cells in the aged.
Avoiding autoimmunity
Unchecked or overactive T
FH cell immune responses have the potential to mount unwarranted germinal centers, composed of aberrantly mutated
B cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s that can drive antibody-mediated
autoimmune disease
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
s. Elevated levels of T
FH-like cells can be detected in the blood of a subset of human patients with
systemic lupus erythematosus
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
(SLE) and
Sjögren syndrome
Sjögren syndrome or Sjögren's syndrome (SjS, SS) is a Chronic disease, long-term autoimmune disease that affects the body's moisture-producing (lacrimal and salivary) glands, and often seriously affects other organ systems, such as the lungs, k ...
.
However, scientific evidence suggesting T
FH cells can definitively cause autoimmunity in humans remains incomplete.
References
{{Lymphocytes
T cells