ICOS Receptor Instructs T Follicular Helper Cell versus Effector Cell Differentiation via Induction of the Transcriptional Repressor BcI6

Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Immunity (Impact Factor: 21.56). 06/2011; 34(6):932-46. DOI: 10.1016/j.immuni.2011.03.023
Source: PubMed


The nature of follicular helper CD4(+) T (Tfh) cell differentiation remains controversial, including the minimal signals required for Tfh cell differentiation and the time at which Tfh cell differentiation occurs. Here we determine that Tfh cell development initiates immediately during dendritic cell (DC) priming in vivo. We demonstrate that inducible costimulator (ICOS) provides a critical early signal to induce the transcription factor Bcl6, and Bcl6 then induces CXCR5, the canonical feature of Tfh cells. Strikingly, a bifurcation between Tfh and effector Th cells was measurable by the second cell division of CD4(+) T cells, at day 2 after an acute viral infection: IL2Rα(int) cells expressed Bcl6 and CXCR5 (Tfh cell program), whereas IL2Rα(hi) cells exhibited strong Blimp1 expression that repressed Bcl6 (effector Th cell program). Virtually complete polarization between Bcl6(+) Tfh cells and Blimp1(+) effector Th cell populations developed by 72 hr, even without B cells. Tfh cells were subsequently lost in the absence of B cells, demonstrating a B cell requirement for maintenance of Bcl6 and Tfh cell commitment via sequential ICOS signals.

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Available from: Youn Soo Choi,
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    • "In this respect, it is of interest that we have not seen a requirement for TCF1 for T FH responses during protein immunization with alum as an adjuvant, which is considered a Th2-inducing condition (T.W., unpublished data). Previous studies have suggested that signaling mediated by CD25 and Blimp1, which are abundantly expressed in early Th1 cells, inhibits T FH cell differentiation (Choi et al., 2011; Johnston et al., 2012; Pepper et al., 2011). Our ChIP and gene expression profiles of Tcf7-deficient T FH cells suggest that TCF1 potentially represses expression of Prdm1 and Il2ra. "
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    Cell Reports 09/2015; 12(12). DOI:10.1016/j.celrep.2015.08.049 · 8.36 Impact Factor
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    • "Following stimulation via the TcR, selective differentiation of T helper cell subsets is dependent on transcription factors, with Bcl-6 being responsible for T follicular helper (Tfh) cell differentiation (Johnston et al., 2009; Choi et al., 2011) and antagonism of other T cell phenotypes (Th1, Th2, Th17). Gene knockout studies in mice have revealed the requirement for CD28 mediatedcostimulation in the upstream control of Tfh differentiation (Linterman et al., 2009), with subsequent signalling through inducible T cell costimulator (ICOS) involved in consolidation of differentiation (Crotty, 2011; Xu et al., 2013). "
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    • "Such intrinsic features or capacity of CD8a À DCs in inducing Tfh cells is not limited to a specific stimulus. A previous study showed that ICOS signals during DC T cell priming instruct Bcl6 expression, leading to CXCR5 expression on CD4 + T cells and thus determine the early bifurcation between Tfh and effector Th cell developments (Choi et al., 2011). However, it was not known that distinct CD8a À DCs upregulate ICOS signals promoting Tfh cell differentiation. "
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