SOX4 and SOX13 control early steps of invariant NKT cell differentiation

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DESCRIPTION (provided by applicant): Invariant NKT (iNKT) cells expressing the canonical V?14-J?18 TCR are central to early immune responses to altered environments potentially damaging to the host. This fast response conditions subsequent activities of diverse lymphoid and myeloid cell subsets. Thus, targeted modulations of iNKT cells have emerged as a potential approach to treat inflammatory disorders as well as enhancing immunity to tumors and vaccines. iNKT cells recognize lipid antigens in the context of the non-classical MHC Class I molecule CD1d. The rapid effector capabilities of iNKT cells, often referred to as "innate-like" responses, are programmed intrathymically and are fundamentally different from the adaptive immunity mediated by the conventional ??T cells. The intrathymic programming of iNKT cell function has been shown to dependent on the signaling of the canonical TCR, and by extension, it has been assumed that TCR signals commit a common precursor of ??T cells to become innate like. However, iNKT cells share molecular features with other innate-like lymphocytes such as ??T cells and genes that control iNKT cell development are modulated by signals other than TCR. We observed that mice lacking the High Mobility Group box (HMG) transcription factors (TFs) Sox4 or Sox13 are impaired in the generation of iNKT and innate-like ??T cell subsets, but not conventional adaptive ??T cells. Both TFs are expressed prior to Tcr gene rearrangements, and in other cell types, combinatorial activities of HMG TFs dictate cell lineage identity and function. Sox13 is exclusively expressed in iNKT and ??TCR+ thymocyte subsets during the programming of effector function and prior to thymic egress. Sox13 is also expressed in half of early T cell progenitors, raising the possibility that Sox13+ progenitors may be biased to generate innate-like effectors expressing either ??TCR or ??TCR. To test this alternate mode of iNKT differentiation, we have developed and validated Sox13 reporter mice. This proposal will determine whether Sox13 and Sox4 function in an innate lymphoid lineage committed precursor to program the rapid effector potential of iNKT cells.