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Several unique waves of ?? T cells are generated solely in the fetal/neonatal thymus, whereas additional ?? T cell subsets are generated in adults. One intriguing feature of ?? T cell development is the coordination of differentiation and acquisition of effector function within the fetal thymus; however, it is less clear whether this paradigm holds true in adult animals. In this study, we investigated the relationship between maturation and thymic export of adult-derived ?? thymocytes in mice. In the Rag2pGFP model, immature (CD24+) ?? thymocytes expressed high levels of GFP whereas only a minority of mature (CD24-) ?? thymocytes were GFP+ Similarly, most peripheral GFP+ ?? T cells were immature. Analysis of ?? recent thymic emigrants (RTEs) indicated that most ?? T cell RTEs were CD24+ and GFP+, and adoptive transfer experiments demonstrated that immature ?? thymocytes can mature outside the thymus. Mature ?? T cells largely did not recirculate to the thymus from the periphery; rather, a population of mature ?? thymocytes that produced IFN-? or IL-17 remained resident in the thymus for at least 60 d. These data support the existence of two populations of ?? T cell RTEs in adult mice: a majority subset that is immature and matures in the periphery after thymic emigration, and a minority subset that completes maturation within the thymus prior to emigration. Additionally, we identified a heterogeneous population of resident ?? thymocytes of unknown functional importance. Collectively, these data shed light on the generation of the ?? T cell compartment in adult mice.

Inhibitory receptors have a critical role in the regulation of immunity. Siglecs are a family of primarily inhibitory receptors expressed by immune cells that recognize specific sialic acid modifications on cell surface glycans. Many tumors have increased sialic acid incorporation. Overexpression of the sialyltransferase ST8Sia6 on tumors led to altered immune responses and increased tumor growth. In this study, we examined the role of ST8Sia6 on immune cells in regulating antitumor immunity. ST8Sia6 knockout mice had an enhanced immune response to tumors. The loss of ST8Sia6 promoted an enhanced intratumoral activation of macrophages and dendritic cells, including upregulation of CD40. Intratumoral regulatory T cells exhibited a more inflammatory phenotype in ST8Sia6 knockout mice. Using adoptive transfer studies, the change in regulatory T cell phenotype was not cell intrinsic and depended on the loss of ST8Sia6 expression in APCs. Thus, ST8Sia6 generates ligands for Siglecs that dampen antitumor immunity.

The nuclear receptors (NR) retinoid X receptors (RXRs) exert immunomodulatory functions to control inflammation and metabolism via homodimers and heterodimers with several other NRs including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers but not heterodimers. Here, we show that in vivo IRX4204 was compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T cell proliferation, reducing T helper 1 differentiation and promoting regulatory T cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-$\gamma$ and TNF-$\alpha$ serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating pro-inflammatory pathways. In vitro, inducible Treg differentiation from na{\{i}}ve CD4+ T cells was enhanced by IRX4204; in vivo IRX4204 increased the conversion of donor Foxp3- T cells into peripheral Foxp3+ Tregs in GVHD mice. Using Foxp3 lineage tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked we demonstrate that IRX4204 supported Treg stability. Despite favoring Tregs and reducing Th1 differentiation IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably IRX4204 reduced in vitro human T cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively these beneficial effects indicate that targeting RXRs with IRX4204 could be used as a novel approach to prevent acute GVHD in the clinic."