Mature natural killer cell and lymphoid tissue–inducing cell development requires Id2-mediated suppression of E protein activity

Abstract

The Id2 transcriptional repressor is essential for development of natural killer (NK) cells, lymphoid tissue–inducing (LTi) cells, and secondary lymphoid tissues. Id2 was proposed to regulate NK and LTi lineage specification from multipotent progenitors through suppression of E proteins. We report that NK cell progenitors are not reduced in the bone marrow (BM) of Id2−/− mice, demonstrating that Id2 is not essential for NK lineage specification. Rather, Id2 is required for development of mature (m) NK cells. We define the mechanism by which Id2 functions by showing that a reduction in E protein activity, through deletion of E2A, overcomes the need for Id2 in development of BM mNK cells, LTi cells, and secondary lymphoid tissues. However, mNK cells are not restored in the blood or spleen of Id2−/−E2A−/− mice, suggesting a role for Id2 in suppression of alternative E proteins after maturation. Interestingly, the few splenic mNK cells in Id2−/− and Id2−/−E2A−/− mice have characteristics of thymus-derived NK cells, which develop in the absence of Id2, implying a differential requirement for Id2 in BM and thymic mNK development. Our findings redefine the essential functions of Id2 in lymphoid development and provide insight into the dynamic regulation of E and Id proteins during this process.

Dendritic cell fate is determined by BCL11A

“…Other Ets/IRF factors do not interact in this fashion (53). Each of these four factors is known to be involved in pDC development or maintenance (45,54), and we have previously confirmed that BCL11A drives both IRF4 and IRF8 expression in mouse pre-B cells (49,55). That BCL11A is recruited to the loci of each of these genes in human pDC CAL-1 chromatin and to evolutionarily conserved EICE-like sites within the promoter regions of itself, ID3, and E2-2/TCF4, places BCL11A near the top of a pDC gene regulatory hierarchy (Fig.…”

“…ID2 and ID3, in particular, have documented roles in murine and human B-cell, T-cell, and pDC biology, and modulate the developmental potential of CDPs and CLPs (23)(24)(25)(26)(27)(28)(29)(30). Though both Id2 and Id3 are coexpressed in purified CDPs (40), only Id3 is detectable in CLPs (49), and notably, differential expression is maintained in the downstream cDC and pDC progeny where cDCs are strongly positive for Id2 but chiefly negative for Id3, and the opposite is true for pDC (40). We have uncovered a role for BCL11A in the transcriptional regulation of ID3, which calls to mind the related identification of ID2 as a target gene repressed by BCL11B (50), a highly similar paralogue of BCL11A essential for T-cell development (2).…”

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…IL‐22 production by ILC3s is critical in containing commensal bacteria,25 and IL‐23‐responsive ILC3s also mediate colitis26 and accumulate in the inflamed intestine of CD patients 27. ILC3s also include the LTi cells involved in organizing tertiary lymphoid structures and tissue repair 28, 29…”

Physiological and Pathological Aspects of Human NK Cells

“…Some of them, like the E proteins, orchestrate a lymphoid-biased cellular context versus myeloid compartment (de Pooter et al, 2010) but must be down-regulated to allow NK cell differentiation (Boos et al, 2007). Other TFs are important both in the NK cell and T cell commitment, such as Notch-1 or Id2 (Benne et al, 2009;Boos et al, 2007).…”