Bcl6 dependent T follicular helper cell differentiation diverges from effector cell differentiation during priming and depends on the gene Icos

By Y. Choi, R. Kageyama, D. Eto, Tania C. Escobar, Robert J. Johnston Jr., L. Monticelli, Christopher Lao, Shane Crotty. Immunity, 2011

932 citations recorded by the source corpus.

SUMMARY The nature of follicular helper CD4+ T (Tfh) cell differentiation remains controversial, including the minimal signals required for Tfh differentiation, and the time at which Tfh differentiation occurs. Here we determine that Tfh 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: IL2Rαint cells expressed Bcl6 and CXCR5 (Tfh cell program), whereas IL2Rαhi 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 hours, 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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/d206541b4a17cb42670396686f2b04881c8922f2

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In Immunology

1. Shane Crotty
2. Carola G. Vinuesa
3. Di Yu
4. J. Sprent
5. O. Boyman
6. W. Leonard
7. Jian-Xin Lin
8. W. Liao

Citations in the corpus

• T follicular helper cell differentiation, function, and roles in disease (2014, background): “ICOSL was found to not be essential on antigen-specific B cells (Xu et al., 2013), but a follow-up study found that ICOSL is normally required on antigen-specific B cells, but that can be overcome when large numbers of antigen-specific B cells are transferred or in the presence of large amounts of a”
• T follicular helper cell biology: A decade of discovery and diseases (2019, background): “The Tfh versus non-Tfh cell fate decision is predominantly made within the first two cell divisions (Choi et al., 2011; 2013; DiToro et al., 2018).”
• Single-cell RNA-seq and computational analysis using temporal mixture modelling resolves Th1/Tfh fate bifurcation in malaria (2017, background): “However, highly immunogenic viral or bacterial infections induced CD4+ T cells to segregate into Bcl6+ (Tfh) or Blimp-1+ (Th1) subpopulations within two days (38, 39).”
• Follicular Helper T Cells. (2016, background): “Intermediate expression of these molecules, particularly CXCR5, PD-1, ICOS, and SAP, marks a stage consistent with pre-GC Tfh cells (52, 55–57).”
• The role of interleukin-2 during homeostasis and activation of the immune system (2012, background): “Two recent studies found that strong IL-2 signals can inhibit the generation of T FH cell”