Figure 1.
Figure 1. Anatomical localization and cellular requirements for Tfh cell generation. (A; i) Naive CD4+ T cells are activated in interfollicular areas or T cell zones of lymphoid tissues after recognition of peptide–MHC class II complexes on DCs. (i) DCs provide signals that up-regulate CXCR5 and down-regulate CCR7 on CD4+ T cells allowing them to migrate to B cell follicles. (ii) At the T cell–B cell border, pre–Tfh cells interact with activated B cells presenting cognate Ag. This results in the pre–Tfh cells delivering help to the B cells, resulting in their differentiation into short-lived extrafollicular plasmablasts or their migration into follicles to form GCs. Ongoing stimulation and Ag presentation provided by B cells drives the full development of Tfh cells. (iii) Within GC, Tfh cells continue to provide help to the B cells, supporting the GC reaction and facilitating the generation of long-lived plasma cells and memory B cells. Reciprocal signals provided by the B cells are also crucial for sustaining the Tfh cells. (B) Initial priming of naive CD4+ T cells by DCs induces expression of Bcl-6 and CXCR5; this requires ICOS/ICOS-L interactions. DCs may produce IL-6 and IL-27, which promote Bcl-6 and c-Maf expression, as well as IL-21 production by CD4+ T cells, in a STAT3-dependent fashion. CXCR5-mediated relocation of Bcl-6+CXCR5+ pre–Tfh cells to the T cell–B cell border allows subsequent interactions with Ag-specific B cells. The Tfh program is imprinted after subsequent interactions with B cells in the GC. The interactions are dependent on the formation of stable T cell–B cell conjugates, which requires CD4+ T cell–intrinsic signaling via SAP-associating receptors (CD84) and involves CD40L/CD40, ICOS/ICOS-L, and CD28/CD86. IL-21 produced by Tfh cells can act in an autocrine manner to maintain Tfh cells at various stages of differentiation. Similarly, B cell–derived IL-6, and possibly IL-27, could contribute to the maintenance of Tfh cells. Tfh cells mediate differentiation of GC B cells into memory and plasma cells via the provision of CD40L and IL-21.

Anatomical localization and cellular requirements for Tfh cell generation. (A; i) Naive CD4+ T cells are activated in interfollicular areas or T cell zones of lymphoid tissues after recognition of peptide–MHC class II complexes on DCs. (i) DCs provide signals that up-regulate CXCR5 and down-regulate CCR7 on CD4+ T cells allowing them to migrate to B cell follicles. (ii) At the T cell–B cell border, pre–Tfh cells interact with activated B cells presenting cognate Ag. This results in the pre–Tfh cells delivering help to the B cells, resulting in their differentiation into short-lived extrafollicular plasmablasts or their migration into follicles to form GCs. Ongoing stimulation and Ag presentation provided by B cells drives the full development of Tfh cells. (iii) Within GC, Tfh cells continue to provide help to the B cells, supporting the GC reaction and facilitating the generation of long-lived plasma cells and memory B cells. Reciprocal signals provided by the B cells are also crucial for sustaining the Tfh cells. (B) Initial priming of naive CD4+ T cells by DCs induces expression of Bcl-6 and CXCR5; this requires ICOS/ICOS-L interactions. DCs may produce IL-6 and IL-27, which promote Bcl-6 and c-Maf expression, as well as IL-21 production by CD4+ T cells, in a STAT3-dependent fashion. CXCR5-mediated relocation of Bcl-6+CXCR5+ pre–Tfh cells to the T cell–B cell border allows subsequent interactions with Ag-specific B cells. The Tfh program is imprinted after subsequent interactions with B cells in the GC. The interactions are dependent on the formation of stable T cell–B cell conjugates, which requires CD4+ T cell–intrinsic signaling via SAP-associating receptors (CD84) and involves CD40L/CD40, ICOS/ICOS-L, and CD28/CD86. IL-21 produced by Tfh cells can act in an autocrine manner to maintain Tfh cells at various stages of differentiation. Similarly, B cell–derived IL-6, and possibly IL-27, could contribute to the maintenance of Tfh cells. Tfh cells mediate differentiation of GC B cells into memory and plasma cells via the provision of CD40L and IL-21.

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