follicular B helper T cells

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.{{cite journal |author=Akiba |title=The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo |journal=J Immunol |volume=175 |issue=4 |pages=2340–8 |date=Aug 2005 |pmid=16081804 |last2=Takeda |first2=K |last3=Kojima |first3=Y |last4=Usui |first4=Y |last5=Harada |first5=N |last6=Yamazaki |first6=T |last7=Ma |first7=J |last8=Tezuka |first8=K |last9=Yagita |first9=H|last10=Okumura |first10=K |display-authors=8 |doi=10.4049/jimmunol.175.4.2340|doi-access=free }} 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.{{cite journal |author=Bauquet |title=The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells |journal=Nat Immunol |volume=10 |issue=2 |pages=167–75 |date=Feb 2009 |pmid=19098919 |doi=10.1038/ni.1690 |last2=Jin |first2=H |last3=Paterson |first3=AM |last4=Mitsdoerffer |first4=M |last5=Ho |first5=IC |last6=Sharpe |first6=AH |last7=Kuchroo |first7=VK |pmc=2742982}}{{cite journal |author=Vogelzang |title=A fundamental role for interleukin-21 in the generation of T follicular helper cells |journal=Immunity |volume=29 |issue=1 |pages=127–37 |date=July 2008 |pmid=18602282 |doi=10.1016/j.immuni.2008.06.001 |last2=McGuire |first2=HM |last3=Yu |first3=D |last4=Sprent |first4=J |last5=MacKay |first5=CR |last6=King |first6=C|doi-access=free }} 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.{{cite journal |author=Ichii |title=Role for Bcl-6 in the generation and maintenance of memory CD8+ T cells |journal=Nat Immunol |volume=3 |issue=6 |pages=558–63 |date=June 2002 |pmid=12021781 |doi=10.1038/ni802 |last2=Sakamoto |first2=A |last3=Hatano |first3=M |last4=Okada |first4=S |last5=Toyama |first5=H |last6=Taki |first6=S |last7=Arima |first7=M |last8=Kuroda |first8=Y |last9=Tokuhisa |first9=T |hdl=20.500.14094/D1002645 |s2cid=2552376 |display-authors=etal|hdl-access=free }}

In germinal centers, antigen-experienced T_FH cells rapidly upregulate the expression of CD40L, which binds and stimulates the B cell surface receptor CD40.{{cite journal|last=Kim|first=JR|author2=Lim, HW |author3=Kang, SG |author4=Hillsamer, P |author5= Kim, CH |title=Human CD57+ germinal center-T cells are the major helpers for GC-B cells and induce class switch recombination.|journal=BMC Immunology|date=Feb 4, 2005|volume=6|pages=3|pmid=15694005|doi=10.1186/1471-2172-6-3|pmc=548684 |doi-access=free }} 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).{{cite journal|last=McHeyzer-Williams|first=M|author2=Okitsu, S |author3=Wang, N |author4= McHeyzer-Williams, L |title=Molecular programming of B cell memory.|journal=Nature Reviews. Immunology|date=Dec 9, 2011|volume=12|issue=1|pages=24–34|pmid=22158414|doi=10.1038/nri3128 |pmc=3947622}} 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.

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.{{cite journal |vauthors=Yusuf I, Kageyama R, Monticelli L, Johnston RJ, Ditoro D, Hansen K, Barnett B, Crotty S | title=Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). | pmid=20525889 | doi=10.4049/jimmunol.0903505 | pmc=2913439 | volume=185 | issue=1 | date=July 2010 | journal=J. Immunol. | pages=190–202}}{{cite journal |vauthors=Ramiscal RR, Vinuesa CG | title=T-cell subsets in the germinal center. | pmid=23405902 | doi=10.1111/imr.12031 | volume=252 | issue=1 | date=March 2013 | journal=Immunol. Rev. | pages=146–55| s2cid=21787025 }} 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.{{cite journal | vauthors=Wollenberg I, Agua-Doce A, Hernández A, Almeida C, Oliveira VG, Faro J, Graca L | title=Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. | pmid=21984700 | doi=10.4049/jimmunol.1101328 | volume=187 | issue=9 | date=November 2011 | journal=J. Immunol. | pages=4553–60| doi-access=free }} 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.{{Cite journal|last1=Schultz|first1=Bruce T.|last2=Teigler|first2=Jeffrey E.|last3=Pissani|first3=Franco|last4=Oster|first4=Alexander F.|last5=Kranias|first5=Gregory|last6=Alter|first6=Galit|author-link6= Galit Alter|last7=Marovich|first7=Mary|last8=Eller|first8=Michael A.|last9=Dittmer|first9=Ulf|date=2016-01-19|title=Circulating HIV-Specific Interleukin-21(+)CD4(+) T Cells Represent Peripheral Tfh Cells with Antigen-Dependent Helper Functions|journal=Immunity|volume=44|issue=1|pages=167–178|doi=10.1016/j.immuni.2015.12.011|issn=1097-4180|pmid=26795249|doi-access=free}}

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,{{cite journal|vauthors=Arifuzzaman M, Rashu R, Leung DT, Hosen MI, Bhuiyan TR, Bhuiyan MS, Rahman MA, Khanam F, Saha A, Charles RC, LaRocque RC, Weil AA, Clements JD, Holmes RK, Calderwood SB, Harris JB, Ryan ET, Qadri F |title=Antigen-specific memory T cell responses after vaccination with an oral killed cholera vaccine in Bangali children and comparison to responses in patients with naturally acquired cholera.|journal=Clinical and Vaccine Immunology|date=August 2012|volume=19|issue=8|pages=1304–11|pmid=22739692|doi=10.1128/CVI.00196-12|pmc=3416086}} a memory T_FH response specifically against cholera antigen had correlated with further antibody production by B cells.

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.{{cite journal|vauthors=Lefebvre JS, Maue AC, Eaton SM, Lanthier PA, Tighe M, Haynes L |title=The aged microenvironment contributes to the age-related functional defects of CD4 T cells in mice.|journal=Aging Cell|date=2012|volume=11|issue=5|pages=732–40|pmid=22607653|doi=10.1111/j.1474-9726.2012.00836.x|pmc=3444657}} This may be in part due to lower CD40L levels on the cell surface of T_FH cells in the aged.{{cite journal|vauthors=Perkey E, Miller RA, Garcia GG |title=Ex vivo enzymatic treatment of aged CD4 T cells restores cognate T cell helper function and enhances antibody production in mice.|journal=J Immunol|date=2012|volume=189|issue=12|pages=5582–9|pmid=23136198|doi=10.4049/jimmunol.1200487|pmc=3518580}}

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.{{cite journal | author=Craft JE.| title=Follicular helper T cells in immunity and systemic autoimmunity.| journal=Nat Rev Rheumatol | volume=8 | year=2012 | pages=337–47 | pmid=22549246 | issue=6 | doi=10.1038/nrrheum.2012.58 | pmc=3604997}} However, scientific evidence suggesting T_FH cells can definitively cause autoimmunity in humans remains incomplete.

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Category:T cells