The SLAM receptor family members SLAM, Ly108, and CD84 are expressed on T cells and B cells and mediate homotypic interactions that lead to adhesion between cells. SLAM can also enhance signaling by the T-cell receptor to augment production of cytokines such as IL-21 that help B cells. The SLAM-associated molecule SAP is a signaling adapter that is required for one SLAM receptor to sustain binding with another. T cells initially express SAP at low levels that are insufficient for sustained adhesion between T and B cells. Fully differentiated TFH cells express high levels of the transcription factor Bcl-6, which induces higher levels of SAP expression. This level is sufficient to sustain cell–cell interactions and allow for the delivery of CD40L and cytokine signals to B cells.
10-4 T cells express surface molecules and cytokines that activate B cells, which in turn promote TFH-cell development.
When TFH cells encounter an activating peptide presented by B cells, the TFH cells respond by expressing receptors and cytokines that in turn activate B cells. As mentioned above, the induced expression of CD40L on TFH cells activates CD40 on B cells to increase B-cell survival, and also induces B-cell expression of co-stimulatory molecules, especially those of the B7 family. Activated T cells also express CD30 ligand (CD30L), which binds to CD30 expressed on B cells and promotes B-cell activation. Mice lacking CD30 show reduced proliferation of activated B cells in lymphoid follicles and weaker secondary humoral responses than normal. TFH cells also secrete several cytokines that regulate B-cell proliferation and antibody production. Primary among these is IL-21, which is produced early in immune responses by TFH cells and which activates the transcription factor STAT3 in B cells to support proliferation and differentiation. IL-21 exerts similar autocrine effects on TFH cells. Later in the antibody response, TFH cells will produce other cytokines, such as IL-4 and IFN-γ, that are characteristic of the other T helper subsets (described in Chapter 9). These will impact B-cell differentiation, particularly class switching, as we discuss later.
The ability of TFH cells to successfully deliver these signals to B cells depends on intimate contact between these cells. Specific adhesion molecules, including several Ig superfamily receptors of the SLAM (signaling lymphocyte activation molecule) family, are involved that prolong and stabilize cell–cell contact. TFH cells and B cells both express SLAM (CD150), CD84, and Ly108, which promote cell adhesion through homotypic binding interactions (Fig. 10.8). The cytoplasmic regions of these SLAM family receptors all interact with an adaptor protein, SAP (SLAM-associated protein), which is expressed highly by TFH cells and which is necessary for prolonging cell–cell contact mediated by these receptors. The SAP gene is inactivated in X-linked lymphoproliferative syndrome, which is associated with a T-cell and NK-cell lymphoproliferative disorder and with a defect in antibody production due to failed interactions between TFH cells and B cells in the germinal center, discussed below. The regulated migration of activated B cells and TFH cells to the same location in the peripheral lymphoid organ increases the chance that linked recognition will occur and deliver appropriate help for B-cell differentiation. Antigen-stimulated B cells that fail to interact with T cells that recognize the same antigen die within 24 hours.