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In prior studies, we and others have found Tim-3 to be expressed on exhausted CD8+ tumor infiltrating lymphocytes (TILs). It was shown that anti-Tim-3 antibody treatment together with anti-PD-1/PD-L1 antibody could abrogate tumor growth and effectively restore T cell effector function to exhausted CD8+ T cells (Sakuishi et al 2010, Fourcade et al 2010, Zhou et al 2011, Ngiow et al 2011). Tim-3 is also expressed on CD4+ TILs but its role in tumor immunity has not been addressed. We have found that the majority of FoxP3+ TILs express Tim-3 in multiple tumor models. Kinetic studies in B16F10 melanoma show that the accumulation of FoxP3+Tim3+ cells parallels tumor growth. Interestingly, this accumulation of FoxP3+Tim-3+ cells is not observed in either the tumor draining lymph node or spleen of tumor-bearing mice, indicating site-specific expansion. FoxP3+Tim-3+ cells are higher producers of IL-10 and are more efficient in suppressing FoxP3- effector T cells in vitro when compared to FoxP3+Tim-3- cells. Depleting FoxP3+ regulatory T cells (Tregs) from established B16 melanoma results in tumor regression and modulation of Tim-3 expression on both FoxP3- CD4 and CD8 TILs. Furthermore, Treg depletion influences the development of exhausted phenotype in CD8+ TILs. This is the first report revealing that the Tim-3+ subset of Tregs predominates within tumor and plays an important role in tumor progression in situ by regulating the functional phenotype of FoxP3- CD4+ and CD8+ TILs.

In vivo control of Mycobacterium tuberculosis (Mtb) reflects the balance between host-immunity and bacterial evasion strategies. Effector TH1 cells that mediate protective immunity by depriving the bacterium of its intracellular niche are regulated in many ways to prevent over-exuberant inflammation. Although Tim3 is generally recognized to down regulate TH1 responses and mediate T cell exhaustion, we recently described that its interaction with Galectin-9 (Gal9) expressed by Mtb infected macrophages (Mϕ) stimulates IL-1β secretion, which is essential for host resistance to Mtb. IL-1β signaling is both necessary for Tim3 mediated Mtb control and sufficient to directly kill Mtb in murine and human Mϕ. The molecular mechanism by which IL-1β restricts bacterial growth is not known. We report that IL-1β kills Mtb through the recruitment of other antimicrobial effector molecules. IL-1β directly augments TNF signaling through increased TNF secretion and TNFR cell surface expression. Furthermore, Tim3/Gal9 and IL-1β activates the executioner caspase-3. Thus, Tim3/Gal9, via IL-1β and downstream TNF production lead to apoptosis and restriction of intracellular Mtb growth. We propose that Tim3/Gal9 interaction acts as a bidirectional molecular rheostat that activates pathways to clear intracellular pathogens in innate immune cells while fine-tuning termination of TH1 responses to prevent immunopathology.