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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    • "Bcl-6 promotes proliferation of T cells444546. Bcl-6 is expressed in Tfh cells at early differentiation in the T-B border, as well as in Tfh cells in the follicles of lymph nodes4748495051. In the progress of CE disease, two types of antigens are exposed to the host immune system and induce the production of antibodies. "
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    ABSTRACT: Background In our study, we investigated whether circulating T follicular helper (Tfh) and the related cytokines are involved in human cystic echinococcosis (CE). Methods A total of 64 patients with CE and 30 healthy controls were enrolled in this study. Percentages of CCR7loPD-1hi cells within CXCR5+ CD4+ T cells (circulating Tfh cells) were detected by flow cytometry. Levels of IL-21 and IL-4 in peripheral blood were detected by cytometric bead array. The mRNA expression of IL-21, IL-4, Bcl-6, and Blimp-1 in peripheral blood mononuclear cells (PBMCs) were measured by real-time PCR. Levels of IgG1, IgG2, IgG3, and IgG4 in the patients’ sera were measured using enzyme-linked immunosorbent assay. Results Percentages of circulating Tfh cells were significantly increased in the CE1, CE2, and CE3 groups (p < 0.05). The concentrations of IL-21 and IL-4 in the serum were significantly increased in CE1, CE2, and CE3 groups (p < 0.05). IL-21 was positively correlated with circulating Tfh cells in CE3 group (r = 0.779, p < 0.05). The mRNA levels of IL-21, IL-4, and Bcl-6 were increased in CE1, CE2, and CE3 groups. Levels of IgG1 and IgG4 in patients’ sera were increased in CE1, CE2, and CE3 groups. Levels of IgG2 and IgG3 were increased in CE4-5 group. Additionally, after stimulation with hydatid fluid in vitro, the levels of circulating Tfh cells, IL-21 and IL-4 in PBMCs isolated from CE patients were significantly increased (p < 0.05). Conclusions The levels of circulating Tfh and related cytokines were significantly increased in CE patients, suggesting that they are involved in human CE.
    Full-text · Article · Dec 2015 · BMC Infectious Diseases
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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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    ABSTRACT: T follicular helper (TFH) and T helper 1 (Th1) cells generated after viral infections are critical for the control of infection and the development of immunological memory. However, the mechanisms that govern the differentiation and maintenance of these two distinct lineages during viral infection remain unclear. We found that viral-specific TFH and Th1 cells showed reciprocal expression of the transcriptions factors TCF1 and Blimp1 early after infection, even before the differential expression of the canonical TFH marker CXCR5. Furthermore, TCF1 was intrinsically required for the TFH cell response to viral infection; in the absence of TCF1, the TFH cell response was severely compromised, and the remaining TCF1-deficient TFH cells failed to maintain TFH-associated transcriptional and metabolic signatures, which were distinct from those in Th1 cells. Mechanistically, TCF1 functioned through forming negative feedback loops with IL-2 and Blimp1. Our findings demonstrate an essential role of TCF1 in TFH cell responses to viral infection.
    Full-text · Article · Sep 2015 · Cell Reports
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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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    ABSTRACT: The production of high affinity, class switched antibodies produced by B cells hinges on the effective differentiation of T follicular helper (Tfh) cells. Here we define conditions specifically enhancing Tfh differentiation and providing protection in a model of influenza infection. Tfh responses were associated with prolonged antigen presentation by dendritic cells (DCs), which maintained T cell/DC interactions into stage 3 (>72 hr) of activation. Blocking stage 3 interactions ablated Tfh generation, demonstrating a causal link between T cell-DC behaviour and functional outcomes. The current data therefore explain how duration of antigen presentation affects the dynamics of T cell-DC interactions and consequently determine Tfh cell differentiation in the developing immune response.
    Full-text · Article · Aug 2015 · eLife Sciences
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