SUMMARY
CD8+ T cells are selected via low affinity interaction with MHC class I molecules on thymic epithelial cells (TECs). However, compromised T cell receptor signaling was proposed to force CD8+ T cell selection on hematopoietic cells through a SLAM-associated protein (SAP)-dependent mechanism similar to NKT cells. The outcome is an unconventional CD8+ T cell with phenotypic and functional characteristics of innate lymphocytes. Here we showed that Id3−/ − CD8+ T cells had an innate-like phenotype and required SAP for their development. However, like conventional CD8+ T cells, Id3−/ − CD8+ thymocytes were selected on TECs. The requirement for SAP and the innate-like phenotype was not intrinsic to Id3−/ − CD8+ thymocytes. Rather, an expanded population of NKT-like cells induced the innate phenotype on CD8+ T cells through production of interleukin-4. Our findings reveal that accumulation of NKT-like cells promotes conventional CD8+ thymocytes to acquire innate lymphocyte characteristics.
BackgroundId3 is a dominant antagonist of E protein transcription factor activity that is induced by signals emanating from the αβ and γδ T cell receptor (TCR). Mice lacking Id3 were previously shown to have subtle defects in positive and negative selection of TCRαβ+ T lymphocytes. More recently, Id3
−/− mice on a C57BL/6 background were shown to have a dramatic expansion of γδ T cells.Methodology/Principal FindingsHere we report that mice lacking Id3 have reduced thymocyte numbers but increased production of γδ T cells that express a Vγ1.1+Vδ6.3+ receptor with restricted junctional diversity. These Vγ1.1+Vδ6.3+ T cells have multiple characteristics associated with “innate” lymphocytes such as natural killer T (NKT) cells including an activated phenotype, expression of the transcription factor PLZF, and rapid production of IFNg and interleukin-4. Moreover, like other “innate” lymphocyte populations, development of Id3
−/− Vγ1.1+Vδ6.3+ T cells requires the signaling adapter protein SAP.ConclusionsOur data provide novel insight into the requirements for development of Vγ1.1+Vδ6.3+ T cells and indicate a role for Id3 in repressing the response of “innate” γδ T cells to SAP-mediated expansion or survival.
The transcription factor LEF1 promotes the expansion and Th2-type polarization of invariant NKT cells in part by directly inducing the expression of the IL-7 receptor component CD127 and the transcription factors c-myc and Gata3.
Invariant natural killer T (iNKT) cells display characteristics of both adaptive and innate lymphoid cells (ILCs). Like other ILCs, iNKT cells constitutively express ID proteins, which antagonize the E protein transcription factors that are essential for adaptive lymphocyte development. However, unlike ILCs, ID2 is not essential for thymic iNKT cell development. Here we demonstrated that ID2 and ID3 redundantly promoted iNKT cell lineage specification involving the induction of the signature transcription factor PLZF and that ID3 was critical for development of TBET-dependent NKT1 cells. In contrast, both ID2 and ID3 limited iNKT cell numbers by enforcing the post-selection checkpoint in conventional thymocytes. Therefore, iNKT cells show both adaptive and innate-like requirements for ID proteins at distinct checkpoints during iNKT cell development.
All innate lymphoid cells (ILCs) require the small helix-loop-helix transcription factor ID2, but the functions of ID2 are not well understood in these cells. We show that mature natural killer (NK) cells, the prototypic ILCs, developed in mice lacking ID2 but remained as precursor CD27CD11b cells that failed to differentiate into CD27CD11b cytotoxic effectors. We show that ID2 limited chromatin accessibility at E protein binding sites near naïve T lymphocyte-associated genes including multiple chemokine receptors, cytokine receptors, and signaling molecules and altered the NK cell response to inflammatory cytokines. In the absence of ID2, CD27CD11b NK cells expressed ID3, a helix-loop-helix protein associated with naïve T cells, and they transitioned from a CD8 memory precursor-like to a naïve-like chromatin accessibility state. We demonstrate that ID3 was required for the development of ID2-deficient NK cells, indicating that completely unfettered E protein function is incompatible with NK cell development. These data solidify the roles of ID2 and ID3 as mediators of effector and naïve gene programs, respectively, and revealed a critical role for ID2 in promoting a chromatin state and transcriptional program in CD27CD11b NK cells that supports cytotoxic effector differentiation and cytokine responses.
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