# Follicular B helper T cells

Follicular helper T cells (also known as T follicular helper cells and abbreviated as T$_{FH}$), are antigen-experienced CD4$^+$ T cells found in the periphery within B cell follicles of secondary lymphoid organs such as lymph nodes, spleen and Peyer's patches, and are identified by their constitutive expression of the B cell follicle homing receptor CXCR5. Upon cellular interaction and cross-signaling with their cognate follicular (Fo B) B cells, T$_{FH}$ cells trigger the formation and maintenance of germinal centers 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 centers, predominantly composed of rapidly dividing B cells 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 cells capable of producing high affinity antibodies against foreign antigen, or germinal center-dependent memory B cells 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-causing mutated B cells in the germinal center. 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 centers. 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 activation of B cell CD40 results in B cell survival and differentiation, including the induction of AID (activation-induced (cytidine) deaminase). 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 during clonal proliferation. The switched antibodies acquire better effector functions, and hypermutated antibody shows greater affinity for antigen.

## Classes of T$_{FH}$ cells

T$_{FH}$ cells formed early in the nascent stages of a germinal center 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, 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-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, encoding for a transcription factor. This small discrete sub-population of cells, called T$_{FR}$ cells (for T Follicular Regulatory cells), is 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-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 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 or the differentiation of effective memory B cells 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 immunizations and vaccine design for the induction of long-term immunity. 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 is largely due to a decline of T cell function, including the capacity for T$_{FH}$ cells to properly support germinal center responses. This may be in part due to lower CD40L 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 cells that can drive antibody-mediated autoimmune diseases. Elevated levels of T$_{FH}$-like cells can be detected in the blood of a subset of human patients with systemic lupus erythematosus (SLE) and Sjögren syndrome. However, scientific evidence suggesting T$_{FH}$ cells can definitively cause autoimmunity in humans remains incomplete.