T_FH cells in bystander and cognate interactions with B cells

Abstract

Summary Follicular T‐helper (TFH) cells play a crucial role in three aspects of the germinal center (GC) response. They promote GC formation, arbitrate competition among GC B cells to determine the outcome of affinity maturation, and regulate GC output of memory and plasma cells to shape the long‐lived humoral immune memory. Of fundamental importance are dynamic physical interactions between TFH and B cells, which are the main platform for TFH cells to deliver “help” factors to B cells and also for reciprocal signaling from B cells to maintain the helper state of TFH cells. Recent work has significantly expanded our understanding of how T‐B interactions are spatiotemporally regulated and molecularly orchestrated to fulfill those TFH functions. In this review, we elaborate two modes of T‐B interactions, the antigen‐specific or cognate mode in which TFH cells engage individual antigen‐presenting B cells and the antigen nonspecific bystander mode in which TFH cells are engaged with the ensemble of follicular B cells. We discuss findings that indicate how short‐lived cognate T‐B contacts coupled with an intercellular positive feedback drive affinity‐based selection and how bystander interactions between T and B cells regulate follicular T‐cell recruitment and maintenance of an appropriate helper state. We argue that this combination of bystander and cognate interactions with B cells constantly shapes the internal state of TFH cells and provides the platform to execute their helper functions.

PDL1 blockage increases fetal resorption and Tfr cells but does not affect Tfh/Tfr ratio and B-cell maturation during allogeneic pregnancy

“…Tfh cells are essential for GC formation and maintenance, and provide survival signals for high affinity B cells within the GC for their differentiation to isotypeswitched antibody secreting cells and memory B cells 38,39 . Although the function of Tfr cells in the GC has not been completely clarified, the mainstream view currently is that Tfr cells restrict Tfh-and B-cell proliferation and exert an inhibitory action on antibody production [40][41][42] .…”

Positive Selection in the Light Zone of Germinal Centers

“…We noted that CD40 expression is elevated in the cMyc + LZ-B cell subpopulation emerging soon after positive selection compared to the cMyc -LZ compartment that contains GC-B cells before positive selection; although this subpopulation largely comprises low-affinity cells at a similar level to that of cMyc -LZ-B cells (50). Increased CD40 expression might allow these GC-B cells to gain more T cell help by these two mechanisms; i) inducible T cell co-stimulator ligand (ICOSL), a ligand for ICOS that is one of the co-stimulatory receptors expressed on TFHs, is induced on GC-B cells through CD40 engagement with CD40L on TFHs and potentiates GC-TFH interactions (51,52); ii) these cells may have an increased chance of interacting with IL-4 expressing TFHs that express CD40L at a higher level than IL-21/IL-4 expressing TFHs or IL-21 expressing TFHs (53). Alternatively, reduction of the engagement of Herpesvirus entry mediator (HVEM) on GC-B cells with a ligand, B-and T-lymphocyte attenuator (BTLA) on TFHs leads to increased expression of CD40L in TFHs (54).…”

Roles of follicular helper and regulatory T cells in allergic diseases and allergen immunotherapy

“…IL‐9 produced by T FH cells has been implicated in supporting memory B‐cell generation in mouse models as well 54 . Besides cytokine signals, the interaction of CD40 ligand (CD40L) on T FH cells with CD40 on B cells is also important for GC B cells to differentiate into memory B cells and plasma cells as revealed by mouse studies 13,55 …”