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Invariant natural killer T (iNKT) cells to date represent the best example of cells known to have a hybrid function, representing both innate and adaptive immunity. Shared phenotypic similarities with NK cells together with a rapid response to a cytokine stimulus and a productive TCR engagement are the features that underline the hybrid nature of iNKT cells. Using these criteria, we provide molecular and functional evidence demonstrating that CD1d-independent (CD1d(ind)) NKT cells, a population of CD1d-unrestricted NKT cells, are endowed with a hybrid function far superior to that of iNKT cells: (i) an extensive shared program with NK cells, (ii) a closer Euclidian distance with NK cells, and (iii) the ability to respond to innate stimuli (Poly:IC) with cytotoxic potential in the same manner as NK cells identify a hybrid feature in CD1d(ind)NKT cells that truly fulfills the dual function of an NK and a T cell. Our finding that CD1d(ind)NKT cells are programmed to act like NK cells in response to innate signals while being capable of adaptive responses is unprecedented, and thus might reemphasize CD1d-unrestricted NKT cells as a subset of lymphocytes that could affect biological processes of antimicrobial and tumor immunity in a unique way.

One unresolved issue in immune tolerance is what prevents self-reactive T cells from activation. In this study, we used a transgenic mouse model of targeted functional inactivation of TGF-βR signaling in CD11c+cells (CD11cdnRmice) and showed a direct impact on the development of experimental autoimmune encephalomyelitis (EAE). We found that MOG35–55immunization of CD11cdnRmice results in strong inflammation of CNS, high frequency of T cells in CNS, increased levels of T helper 1 (TH1) and TH17 cytokines in the periphery, and lack of remission from EAE. Once crossed with mice prone to autoimmunity, double-transgenic CD11cdnRMogTCRmice revealed a spontaneous EAE-like disease characterized by early infiltration of activated myelin-specific T cells into CNS, activation of microglial cells, inflammation of CNS, dysfunction of locomotion, and premature death. We constructed chimeric mice and demonstrated that inactivation of TGF-βR signaling in dendritic cells (DCs) results in augmented EAE-associated T cell responses. Our data provide direct evidence that TGF-β can control autoimmunity via actions on DCs.

CD4+CD25+regulatory T cells are essential in the protection from organ-specific autoimmune diseases. In the pancreas, they inhibit actions of autoreactive T cells and thereby prevent diabetes progression. The signals that control the generation, the maintenance, or the expansion of regulatory T cell poolin vivoremain poorly understood. Here we show that a transient pulse of transforming growth factor β (TGF-β) in the islets during the priming phase of diabetes is sufficient to inhibit disease onset by promoting the expansion of intraislet CD4+CD25+T cell pool. Approximately 40–50% of intraislet CD4+T cells expressed the CD25 marker and exhibited characteristics of regulatory T cells including small size, high level of intracellular CTLA-4, expression of Foxp3, and transfer of protection against diabetes. Results fromin vivoincorporation of BrdUrd revealed that the generation of a high frequency of regulatory T cells in the islets is due toin situexpansion upon TGF-β expression. Thus, these findings demonstrate a previously uncharacterized mechanism by which TGF-β inhibits autoimmune diseases via regulation of the size of the CD4+CD25+regulatory T cell poolin vivo.