Soluble Tim-3 is shed from CD8+ T cells by the sheddase ADAM10, is increased in plasma during untreated HIV infection, and correlates with HIV disease progression (VIR6P.1165)

Abstract

Abstract Chronic HIV infection results in a loss of HIV-specific CD8+ T cell effector function, termed “exhaustion”, mediated, in part, by the co-inhibitory receptor T cell immunoglobulin mucin domain-3 (Tim-3). Like many other receptors, a soluble form of this protein has been described in human blood plasma. However, soluble Tim-3 (sTim-3) is poorly characterized and its role in HIV disease is unknown. Here we show that Tim-3 is shed from the surface of responding CD8+ T cells by the matrix metalloproteinase, ADAM10, producing a soluble form of the co-inhibitory receptor. Despite previous reports in the mouse model, no alternatively spliced, soluble form of Tim-3 was observed in humans. Shed sTim-3 was found in human plasma, and was significantly elevated during early and chronic untreated HIV infection, but was not found differentially modulated in HAART treated HIV-infected subjects or in elite controllers, when compared to HIV-uninfected subjects. Plasma sTim-3 levels positively correlated with HIV viral load and negatively correlated with CD4 counts. Thus, plasma sTim-3 shedding correlated with HIV disease progression. Despite these correlations, we found that shedding Tim-3 did not improve the function of CD8+ T cells in terms of IFN-γ production or prevent their apoptosis through galectin-9. Further characterization studies of sTim-3 function are needed to understand the contribution of sTim-3 in HIV disease pathogenesis with implications for novel therapeutic interventions.