Follicular B helper T cells

Classes of TFH 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 portion circulate in the blood and are termed peripheral T helper cells (T_PH). These cells share traits with T_FH cells such as secretion of IL-21 upon stimulation. However, they do not possess the chemokine receptor CXCR5 to the same degree as T_PH cells. This is because they express low levels of the T_FH-defining transcription factor Bcl-6. Lack of Bcl-6 means that other transcription factors are expressed at higher levels, leading to heightened expression of chemokines associated with movement into the tissues rather than remaining in a secondary lymphoid organ. In accordance with their presence in the tissue their effector function is limited to memory B cells unlike T_FH cells which can help both naïve and memory B cells. T_PH typically express similar levels of Inducible T cell co-stimulator (ICOS) compared to T_FH cells. ICOS is a member of the CD28/B7 superfamily and provides essential co-stimulatory signals to activated T cells. T_PH cells appear to contribute to early life immunity as well as during acute viral infection however they play a major role in chronic inflammation and autoimmune disorders such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE).

At the site of chronic inflammation, such as in synovium of people with RA, T_PH cells contribute to the creation of tertiary lymphoid structure (TLS). TLS are ectopic lymphoid aggregates that can form in non-lymphoid tissue during chronical inflammation, for example in auto immune diseases or cancer. TLS arise through chemokine-driven recruitment of immune cells, including T cells, B cells and dendritic cells (DCs) which cluster tightly. TLS often contain high endothelial venules (HEVs), a type of vessel important for lymphocyte entry. TLSs can be classified as early aggregates, immature TLSs containing follicular DCs network and mature TLS containing a germinal center. In many cancer types TLS correlate with better prognosis for cancer patients, as they seem to enhance anti-tumor response of the immune system. In autoimmunity TLS often sustain chronic inflammation. T_PH cells in RA secrete high levels of the chemokine CXCL13 which recruits B cells where T_PH carry out their function of activating memory B cells . This causes persistent antibody production and maintenance of high levels of B cells and inflammation. T_PH cells play a role in SLE as peripheral blood samples from people with SLE have higher counts of T_PH cells which is associated with higher levels of Type-I interferons and proinflammatory cytokines and greater migration into the skin and kidneys. T_PH from people with SLE also have higher levels of ICOS than normal which suggests that greater co-stimulatory signaling of activated T_PH cells contributes to autoimmunity and chronic inflammation.

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.

Role in Cancer

T_FH play a fundamental role in antitumor immunity by localizing predominantly within mature tertiary lymphoid structures (mTLS), where they facilitate structural organization and interaction between T and B lymphocytes. These cells are essential for the formation of functional germinal centers and the B-cell isotype switching (class switching) process, which enables a more mature and experienced humoral response against the tumor. In the context of non-small cell lung cancer (NSCLC) treated with neoadjuvant chemoimmunotherapy, a higher proportion of Tfh cells within mature TLS is directly associated with achieving a complete pathologic response

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.