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, Oct 01, 2015
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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FH responses during protein immunization with alum as an adjuvant, which is considered a Th2-inducing condition (T.W., unpublished data).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.
    Cell Reports 09/2015; 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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    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 hours) 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.
    eLife Sciences 08/2015; 4. DOI:10.7554/eLife.06994 · 9.32 Impact Factor
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    • "Previous studies in mouse models demonstrated the importance of ICOS ligand (ICOSL) expressed by DCs for the differentiation of Tfh cells (Choi et al., 2011). "
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    ABSTRACT: Increased activity of T follicular helper (Tfh) cells plays a major pathogenic role in systemic lupus erythematosus (SLE). However, the mechanisms that cause aberrant Tfh cell responses in SLE remain elusive. Here we showed the OX40 ligand (OX40L)-OX40 axis contributes to the aberrant Tfh response in SLE. OX40L was expressed by myeloid antigen-presenting cells (APCs), but not B cells, in blood and in inflamed tissues in adult and pediatric SLE patients. The frequency of circulating OX40L-expressing myeloid APCs positively correlated with disease activity and the frequency of ICOS(+) blood Tfh cells in SLE. OX40 signals promoted naive and memory CD4(+) T cells to express multiple Tfh cell molecules and were sufficient to induce them to become functional B cell helpers. Immune complexes containing RNA induced OX40L expression on myeloid APCs via TLR7 activation. Our study provides a rationale to target the OX40L-OX40 axis as a therapeutic modality for SLE. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 06/2015; 42(6). DOI:10.1016/j.immuni.2015.05.012 · 21.56 Impact Factor
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