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Review
, 38 (3), 195-201

Life of T Follicular Helper Cells

Affiliations
Review

Life of T Follicular Helper Cells

Woong-Kyung Suh. Mol Cells.

Abstract

Antibodies are powerful defense tools against pathogens but may cause autoimmune diseases when erroneously directed toward self-antigens. Thus, antibody producing cells are carefully selected, refined, and expanded in a highly regulated microenvironment (germinal center) in the peripheral lymphoid organs. A subset of T cells termed T follicular helper cells (Tfh) play a central role in instructing B cells to form a repertoire of antibody producing cells that provide life-long supply of high affinity, pathogen-specific antibodies. Therefore, understanding how Tfh cells arise and how they facilitate B cell selection and differentiation during germinal center reaction is critical to improve vaccines and better treat autoimmune diseases. In this review, I will summarise recent findings on molecular and cellular mechanisms underlying Tfh generation and function with an emphasis on T cell costimulation.

Keywords: T follicular helper; antibody; costimulation; germinal center.

Figures

Fig. 1.
Fig. 1.
(A) B cell selection in the GC is facilitated by competition for Tfh. B cells undergo clonal expansion in the dark zone of GC. B cells that have gained high affinity antibody on the surface compete better in the light zone to receive “help” form Tfh and further differentiate into memory B cells or antibody-secreting plasma cells; other clones undergo apoptosis. (B) Life of Tfh. Pre-Tfh cells arise during DC-mediated priming phase under optimal polarization conditions (Stage 1, day 1–3 post-immunization or infection). Pre-Tfh migrate to the B cell follicle guided by chemokine gradient and find cognate B cells in the plethora of non-cognate B cells (Stage 2, day 4–6). Only stable conjugates of T-B pairs sharing antigen-specificity move into the GC. Around day 7–10, mature Tfh cells are found in GC interacting with B cells (Stage 3). Some of the GC Tfh (and pre-Tfh cells) may get into circulation to form memory-like Tfh pool (Stage 4).
Fig. 2.
Fig. 2.
Molecular components controlling Tfh generation and function. (A) CD4 T cells possessing higher affinity TCR under the influence of costimulation (CD28 and ICOS) and cytokine milieu (IL-6 and IL-21 in mice; IL-12 in humans) become pre-Tfh (Bcl6+, CXCR5+, CCR7low). (B) Pre-Tfh should continuously move around in the T-B border until they encounter cognate B cells. ICOSL-expressing non-cognate B cells facilitate the motile behavior of pre-Tfh at the T-B border in an antigen-independent manner. Afterwards, SAP-dependent signaling induced by SLAM family receptors (such as CD84) promote the formation of stable T-B conjugates. Defects in any of these two components stall pre-Tfh at the T-B border and GC reaction is severely affected. (C) Mature GC Tfh cells (Bcl6++, CXCR5++, PD-1++) make rather short-lasting yet entangled contact with cognate B cells in the GC. At this time, ICOS and CD40 signaling axes form a feedforward circuit that should allow focused delivery of key helper cytokines such as IL-4 and IL-21. GC Tfh cells can visit other GCs but the residence time of GC Tfh in an individual GC can be regulated by cooperative functions of CXCR5 and S1PR2.

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