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.
Innate immune responses have been broadly associated with the myeloid lineage cells that are swiftly activated by pathogen or damage-associated molecules. This first order reaction also involves lymphocytes, with NK cells as the best characterized fast responders to viral infections. While innate lymphocytes were initially classified as those not expressing clonotypic antigen receptors generated by the RAG-mediated somatic recombinations it is now apparent that diverse lymphoid cell subsets mediate innate immunity that cannot be correlated to the type of antigen receptors expressed. Two classic TCR+ innate lymphocytes are alphabetaTCR+ invariant NKT (iNKT) and gammadeltaTCR+ T cells. Both are activated within hours of pathogen challenge and depending on tissue locales and the state of cells that activate them, each can perform several possible effector functions. iNKT cells that are elicited to make IL-10 promote immune suppression and strategies have been developed to favor the expansion of this subset of iNKT cells in animals to treat autoimmunity. Conversely, IFN? producing iNKT cells prime immune responses with cytotoxic and inflammatory biases, permitting recognition of altered self (tumors) as well as amplifying immunity against pathogens. While several clinical trials are ongoing to manipulate iNKT cells in various disease settings, such as asthma and cancer, many fundamental questions regarding how iNKT cells are made remain. One central issue is the possibility that iNKT cells acquire innate immune function not because they are instructed by the TCR alone, but rather iNKT cells arise from precursors that are intrinsically biased to become innate-like. We found that the two transcription factors, Sox4 and Sox13, expressed early in T cell progenitors are necessary for iNKT cell development. They also control other innate lymphoid effector generation, but Sox13 is not expressed in adaptive lymphocytes and Sox4 is dispensable for conventional alpha/beta T cell development. Early T cell progenitors are heterogeneous and can be segregated based on Sox13 expression. This proposal will determine the molecular origin of iNKT cells by testing whether Sox13+ progenitors preferentially generate iNKT cells. Preprogramming of innate effector function by novel gene regulatory networks will require revisions to the current theory of T cell development and provide new targets for immunotherapies designed to manipulate iNKT cells and their functionally related lymphoid effector subsets.
| Kang, Joonsoo; Malhotra, Nidhi (2015) Transcription factor networks directing the development, function, and evolution of innate lymphoid effectors. Annu Rev Immunol 33:505-38 |
