The E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c-myc/p19Arf pathways to suppress innate variant TFH cell development, thymocyte expansion, and lymphomagenesis.

Masaki Miyazaki,Yasutoshi Agata,Hiroshi Kawamoto,Keisuke Wagatsuma,Nissi Varki,Vivek Chandra,Kazuko Miyazaki,Aaron N Chang,Hans-Reimer Rodewald,Cornelis Murre,Shuwen Chen,Rintaro Saito

doi:10.1101/gad.255331.114

Abstract

It is now well established that the E and Id protein axis regulates multiple steps in lymphocyte development. However, it remains unknown how E and Id proteins mechanistically enforce and maintain the naïve T-cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate variant follicular helper T (TFH) cells. Innate variant TFH cells required major histocompatibility complex (MHC) class I-like signaling and were associated with germinal center B cells. We found that Id2 and Id3 induced Foxo1 and Foxp1 expression to antagonize the activation of a TFH transcription signature. We show that Id2 and Id3 acted upstream of the Hif1a/Foxo/AKT/mTORC1 pathway as well as the c-myc/p19Arf module to control cellular expansion. We found that mice depleted for Id2 and Id3 expression developed colitis and αβ T-cell lymphomas. Lymphomas depleted for Id2 and Id3 expression displayed elevated levels of c-myc, whereas p19Arf abundance declined. Transcription signatures of Id2- and Id3-depleted lymphomas revealed similarities to genetic deficiencies associated with Burkitt lymphoma. We propose that, in response to antigen receptor and/or cytokine signaling, the E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c-myc/p19Arf pathways to control cellular expansion and homeostatic proliferation.

Highlights

The differentiation of T-lineage cells is initiated in the thymus
Previous studies have demonstrated that Id3 expression is induced at the pre-TCR checkpoint and further elevated during the positive selection process, whereas Id2 expression is low in positively selected DP cells but elevated in CD4SP or CD8SP cells (Bain et al 2001; Engel et al 2001; Miyazaki et al 2011; Jones-Mason et al 2012)
We found that a large fraction of CD4SP and DN TCRb+ as well as invariant natural killer T (iNKT) cells expressed CXCR5, PD-1, and ICOS in thymi derived from 5-wk-old Id2fl/flId3fl/flIL7RCre mice (Fig. 1B; Supplemental Fig. 1A,B)

Summary

Introduction

Soon after arriving in the thymus, T-cell progenitors initiate TCRb locus rearrangement, undergo limited expansion, and initiate a T-lineage-specific pro-. The selection process permits the developmental progression of a selected group of adaptive T-lineage cells that have acquired a TCR with moderate affinity for major histocompatibility complex (MHC) class II (CD4 single positive [CD4SP]) or class I (CD8SP) associated with self-antigens (Klein et al 2014). Adaptive B and T cells express an enormously diverse antigen receptor repertoire. They maintain a naıve lymphoid cell state until they encounter invading pathogens, upon which they expand and differentiate into effector cells. Innate lymphoid cells (ILCs) carry germline-encoded receptors or express a limited antigen receptor repertoire and have the potential to rapidly induce cytokine expression (Cerutti et al 2013; Verykokakis et al 2014). ILCs act primarily by modulating the activities of adaptive immune cells

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Conclusion