ICOS signaling is required for inhibition of the transcription factor Klf2, which controls expression of genes expressed by follicular T helper (Tfh) cells. When ICOS signaling is blocked, Tfh cells lose expression of characteristic Tfh genes and revert to an effector phenotype, resulting in disruption of the germinal center response.

After being activated by antigen, helper T lymphocytes switch from a resting state to clonal expansion. This switch requires inactivation of the transcription factor Foxo1, a suppressor of proliferation expressed in resting helper T lymphocytes. In the early antigen-dependent phase of expansion, Foxo1 is inactivated by antigen receptor-mediated post-translational modifications. Here we show that in the late phase of expansion, Foxo1 was no longer post-translationally regulated but was inhibited post-transcriptionally by the interleukin 2 (IL-2)-induced microRNA miR-182. Specific inhibition of miR-182 in helper T lymphocytes limited their population expansion in vitro and in vivo. Our results demonstrate a central role for miR-182 in the physiological regulation of IL-2-driven helper T cell-mediated immune responses and open new therapeutic possibilities.

T-follicular helper (TFH) cells represent the subpopulation of CD4+ T cells that provides help for antigen-specific B cells in the GC response. They are generated from naïve T cells during an immune response and are imprinted by their master transcription factor Bcl-6. It has been a long-standing question if TFH cells contribute to the CD4 + memory pool after the GC response has been terminated. To answer this question, we sorted antigen-specific TFH and non-TFH effector cells from an ongoing GC response and transferred them into naïve mice. Without further signals via the TCR, transferred cells rapidly contracted with a small population of both TFH and non-TFH cells surviving as memory cells in peripheral lymphoid organs for at least 4 weeks in the absence of antigen. TFH cells strongly downregulated their signature genes Bcl-6, CXCR5, and PD-1 in the memory phase. Upon rechallenge with antigen they rapidly upregulated these markers again. An enhanced potential to produce IL-21, paired with higher expression of CXCR5 and lower expression of CCR7, should enable TFH memory cells to provide more efficient help for antigen-specific B cells than their non-TFH counterparts. Immunol. 2012Immunol. . 42: 1981Immunol. -1988 a critical role for the generation of B-cell memory [3]. However, one fundamental question remains: Can TFH cells themselves survive as long-term memory cells as it has been shown for other T-cell subsets [4] or do they simply die after the GC reaction they supported has come to an end? We addressed this important question by sorting antigenspecific TFH cells directly from an ongoing GC response and transferring them into naïve mice. Memory cells derived from these TFH cells were characterized in the memory phase and after rechallenge with antigen. Keywords Results TFH cells require continuous antigen-stimulation for their maintenanceTo analyze the fate of antigen-specific TFH cells, we used an adoptive transfer system with TCR-transgenic cells from either OT-II mice [5] specific for ovalbumin or Smarta mice [6] that have a TCR recognizing a peptide from lymphocytic choriomeningitis virus (LCMV). Expression of the congenic marker Thy-1.1 on the transgenic T cells allows nonambiguous identification of even very small numbers of antigenspecific T cells and sorting of cells without cross-linking their TCR. C57BL/6 recipients of transgenic T cells were injected s.c. with the cognate antigen in CFA. In this system, upregulation of Bcl-6 within CD4 + T cells in the draining lymph node could be observed as early as 48 h after immunization (as reported by others [7,8]; data not shown). By day 5, a distinct population of cells with very high expression of PD-1 and CXCR5, two markers commonly used for defining TFH cells [9], could be clearly identified. The absolute number of TFH cells in the draining lymph node peaked around day 8 and slowly declined afterwards in parallel with the contraction of the GC response (data not shown). At day 8, the TFH phenotype should be fully imprinted and we therefore used th...