The immunoregulatory protein T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates T cell exhaustion and contributes to the suppression of immune responses in both viral infections and tumors. Tim-3 blockade reverses the exhausted phenotype of CD4+ and CD8+ T cells in several chronic diseases including melanoma. Interestingly, natural killer (NK) cells constitutively express Tim-3; however, its role in modulating the function of these innate effector cells remains unclear, particularly in human disease. In this study, we compared the function of Tim-3 in NK cells from healthy donors and patients with metastatic melanoma. NK cells from the latter were functionally impaired/exhausted and Tim-3 blockade reversed this exhausted phenotype. Moreover, Tim-3 expression levels correlated with the stage of the disease and poor prognostic factors. These data indicate that Tim-3 can function as an NK cell exhaustion marker in advanced melanoma and supports the development of Tim-3-targeted therapies to restore antitumor immunity.
Dendritic cells (DC) play a central role in the induction of immunity and also in tolerance in their role as professional antigen-presenting cells (APC). In the absence of DC, a fatal autoimmunity develops in animal models. While the role of DC has been investigated extensively in the pathogenesis of Rheumatoid arthritis (RA), it remains unclear if DC initiate autoimmunity in this disease. Nevertheless, evidence points towards a significant role for DC in its maintenance and progression. Current biological therapies of RA are designed to ameliorate disease by targeting downstream products of APC such as TNFα, IL-1 and IL-6. Emerging therapies for RA are exploiting the tolerogenic capacity of DC. "Tolerogenic" DC can be generated from myeloid precursors ex vivo, loaded with antigen and manipulated to suppress autoimmune responses in vivo, through the induction of activation induced cell death (AICD), anergy, and/or regulatory T cells. Cells that are primed by DC such as B cells, T helper (Th)-1(Th1) and Th17 cells, and which have been implicated in certain models of autoimmunity, are also being considered as additional targets for immune based therapy. Studies to validate these approaches to ameliorate autoimmunity will be necessary before they are applied in the clinic.
Acute HIV-1 infection results in dysregulated immunity, which contributes to poor control of viral infection. DCs are key regulators of both adaptive and innate immune responses needed for controlling HIV-1, and we surmised that factors elicited during acute HIV-1 infection might impede DC function. We derived immature DCs from healthy donor peripheral blood monocytes and treated them with plasma from uninfected control donors and donors with acute HIV-1 infections. We found that the plasma from patients with HIV specifically inhibited DC function. This suppression was mediated by elevated apoptotic microparticles derived from dying cells during acute HIV-1 infection. Apoptotic microparticles bound to and inhibited DCs through the hyaluronate receptor CD44. These data suggest that targeting this CD44-mediated inhibition by apoptotic microparticles could be a novel strategy to potentiate DC activation of HIV-specific immunity.
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