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

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 (T FH ) cells. Innate variant T FH 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 T FH 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 ab 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.

Id3 Orchestrates Germinal Center B Cell Development

“…Thus, it appears that the regulation of Ccr6 by the E2A/Id3 axis is conserved between human and murine germinal center B cells. More recent studies have indicated that depletion of both Id2 and Id3 expression in T lineage cells leads to the rapid development of T cell lymphoma (20). Is Id3 expression also essential to suppress the development of lymphoma in mice?…”

“…ϩ innate ␥␦ T cells, and innate variant T FH cells (20)(21)(22)(23)(24)(25)(26). The intrinsic roles of Id proteins in B cell development have not been examined in great detail.…”

“…Specifically, in developing T cell progenitors, they enforce the pre-T cell receptor (pre-TCR), ␥␦ TCR, and ␣␤ TCR checkpoints (16)(17)(18)(19)(20). Id3-deficient mice are closely associated with the development of CXCR5 ϩ T follicular helper-like (T FHlike) cells and CXCR5 ϩ effector regulatory T cells (Treg) (17,20,21). Finally, Id2 and Id3 act in the thymus to suppress the development and expansion of invariant NKT (iNKT) cells, V␥1.1…”

Dimerization-driven degradation of C. elegans and human E proteins

“…The best characterized is the negative regulatory mechanism involving expression of Drosophila Emc or mammalian Id, which contain an HLH domain but no DNA-binding domain: Emc/Id forms a heterodimer with E that cannot bind DNA, thereby acting as dominant-negative to reduce E activity (Benezra et al 1990;Ellis et al 1990). Id regulates E in diverse developmental and physiological processes, and how it regulates E continues to be investigated (Ling et al 2014;Miyazaki et al 2015). In addition, in some contexts, E proteins may stabilize their dimerization partners (Viñals et al 2004;Roark et al 2012).…”

Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells

“…However, after a presumed second hit, lymphoma cells have enrichment for genes often dysregulated in cancers, cytokine-cytokine interaction genes and Nf-κB signaling, similar to pathways reported in human NK/T tumors. Similarly, deficiency of Id2 and/or Id3 in mice also causes an expansion of innate variant T FH -like cells, and ab T cell lymphomas in these Id2/Id3-deficient mice that display an increase in Myc expression and reduction in the tumor suppressor Cdkn2a [88,110]. There is evidence to suggest tumor suppressor functions of Id4 in T cell tumors.…”