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B lymphocytes differentiate into antibody-secreting cells under the antigen-specific control of follicular helper T cells (T(FH) cells). Here we demonstrate that isotype-switched plasma cells expressed major histocompatibility complex (MHC) class II, the costimulatory molecules CD80 and CD86, and the intracellular machinery required for antigen presentation. Antigen-specific plasma cells accessed, processed and presented sufficient antigen in vivo to induce multiple helper T cell functions. Notably, antigen-primed plasma cells failed to induce interleukin 21 (IL-21) or the transcriptional repressor Bcl-6 in naive helper T cells and actively decreased these key molecules in antigen-activated T(FH) cells. Mice lacking plasma cells showed altered T(FH) cell activity, which provided evidence of this negative feedback loop. Hence, antigen presentation by plasma cells defines a previously unknown layer of cognate regulation that limits the antigen-specific T(FH) cell program that controls ongoing B cell immunity.

Clonal evolution underpins all facets of adaptive immunity. In particular, antigen-specific helper T (Th) cell development is central to high-affinity B cell immunity and protective vaccination. Dendritic cell maturation and TCR affinity-based selection mechanisms control the recruitment and effective propagation of preferred antigen-specific Th cell cohorts in local lymphoid tissue. Importantly, follicular B helper T (T(FH)) cells emerge as the specialized local effector Th cells that orchestrate the stepwise development of B cell immunity in these local environments. Recent studies also introduce the role of persistent antigen in the development of effector Th cells with evidence for long-term antigen depots that might contribute to local antigen-specific Th cell memory.

Migration of antigen-activated CD4 T cells to B cell areas of lymphoid tissues is important for mounting T cell-dependent antibody responses. Here we show that CXC chemokine receptor (CXCR)5, the receptor for B lymphocyte chemoattractant (BLC), is upregulated on antigen-specific CD4 T cells in vivo when animals are immunized under conditions that promote T cell migration to follicles. In situ hybridization of secondary follicles for BLC showed high expression in mantle zones and low expression in germinal centers. When tested directly ex vivo, CXCR5(hi) T cells exhibited a vigorous chemotactic response to BLC. At the same time, the CXCR5(hi) cells showed reduced responsiveness to the T zone chemokines, Epstein-Barr virus-induced molecule 1 (EBI-1) ligand chemokine (ELC) and secondary lymphoid tissue chemokine (SLC). After adoptive transfer, CXCR5(hi) CD4 T cells did not migrate to follicles, indicating that additional changes may occur after immunization that help direct T cells to follicles. To further explore whether T cells could acquire an intrinsic ability to migrate to follicles, CD4(-)CD8(-) double negative (DN) T cells from MRL-lpr mice were studied. These T cells normally accumulate within follicles of MRL-lpr mice. Upon transfer to wild-type recipients, DN T cells migrated to follicle proximal regions in all secondary lymphoid tissues. Taken together, our findings indicate that reprogramming of responsiveness to constitutively expressed lymphoid tissue chemokines plays an important role in T cell migration to the B cell compartment of lymphoid tissues.