T Follicular Helper Cell

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.

References

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T cells