Cell autonomous expression of BCL6 is required to maintain lineage identity of mouse CCR6+ ILC3s

Abstract

Innate lymphoid cells (ILC) are similar to T helper (Th) cells in expression of cytokines and transcription factors. For example, RORγt is the lineage-specific transcription factor for both ILC3 and Th17 cells. However, the ILC counterpart for BCL6-expressing T follicular helper (Tfh) cells has not been defined. Here, we report that in the ILC compartment, BCL6 is selectively co-expressed with not only CXCR5 but also RORγt and CCR6 in ILC3 from multiple tissues. BCL6-deficient ILC3 produces enhanced levels of IL-17A and IL-22. More importantly, phenotypic and single-cell ATAC-seq analysis show that absence of BCL6 in mature ILC3 increases the numbers of ILC1 and transitional cells co-expressing ILC3 and ILC1 marker genes. A lineage-tracing experiment further reveals BCL6+ ILC3 to ILC1 trans-differentiation under steady state. Finally, microbiota promote BCL6 expression in colonic CCR6+ ILC3 and thus reinforce their stability. Collectively, our data have demonstrated that CCR6+ ILC3 have both Th17 and Tfh programs and that BCL6 expression in these cells functions to maintain their lineage identity.

BCL6 promotes a stem-like CD8 + T cell program in cancer via antagonizing BLIMP1

“…We next further assessed the differentiation potential of BCL6 + T cells in cancer by tracing the fate of Bcl6 CreERT2 × Rosa26 tdTomato OT-I cells (Fig. 1D) ( 34 ). Results showed that although all tdTomato + OT-I cells originally expressed LY108 but not TIM-3, during E.G7 tumor development a portion of them turned into LY108 − TIM-3 + T term cells (Fig.…”

“…C57BL/6, CD45.1, Tcrbd −/− , OT-I (TCR specific for E.G7 and B16-OVA K b OVA 257–264 ), and P14 (TCR specific for LCMV D b GP 33–41 ) congenic mice were maintained in house. Bcl6 CreERT2 mice ( 34 ) were crossed with Rosa26 tdTomato mice. Bcl6 fl/fl mice ( 48 ), Tgfbr2 fl/fl mice ( 62 ), Tcf7 fl/fl mice ( 40 ), and Prdm1 fl/fl mice ( 63 ) were crossed with Cd8a Cre mice ( 64 ).…”

“…A total of 1 × 10 6 E.G7 and 2 × 10 5 B16-OVA cells expressing OVA 257-264 were injected subcutaneously into mice. A total of 2 × 10 6 plaque-forming units of LCMV clone13-expressing GP [33][34][35][36][37][38][39][40][41] were injected intravenously into mice. Tumor volume was calculated as follows: tumor volume = π × length × width 2 / 6.…”

Group 1 ILCs: Heterogeneity, plasticity, and transcriptional regulation

“…68 BCL6 appears to regulate the ILC3 program, including RORγt expression and IL17 and IL22 production as BCL6 deficient ILC3s have increased RORγt expression and altered type 3 cytokine production. 68,69 With respect to the ILC1 program, one study reported that BCL6 expression positively regulates the group1 ILC program, whereas another study reported that BCL6 deficiency in ILC3s resulted in induction of the ILC1 program and promoted ILC3 to ILC1 transition. 66,68 These differences could be due to the different mouse strains used in these studies.…”

We are memory: B‐cell responses in allergy and tolerance

“…Due to their plasticity, they may also exert Tfh-like functions needed for the establishment of high-affinity matured B mem and plasma cells. While this seems especially the case for IL-17-producing cells, there are also data pointing to IL-4-producing type 2 TC and ILC, namely LTi/CCR6 + ILC3 [34,40,45,46].…”