TIMs: central regulators of immune responses

Abstract

Exhaustion of T cell responses during chronic viral infections has been observed in both mouse and man and has been attributed to up-regulation of PD-1 on the surface of exhausted T cells. In patients with chronic human HIV infection, T cell exhaustion leads to opportunistic infections associated with AIDS. However, not all the exhausted T cells express PD-1, suggesting that other molecules may be involved in the phenotype. A new study now demonstrates a central role for T cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) in T cell exhaustion during chronic HIV infection and suggests that TIM-3 may be a novel therapeutic target in chronic viral diseases.

Figure 1.

Differential expression of TIM-3 on the surface of T cells regulates susceptibility to viral infection or development of autoimmune injury. (A) In patients with progressive HIV infection, TIM-3 is up-regulated on the surface of CD4 and CD8 T cells. Up-regulation of TIM-3 on HIV-specific CD8 T cells leads to impaired cell survival, proliferation, and cytokine production (1). Blocking TIM-3 binding to its ligand galectin-9 using soluble TIM-3 or TIM-3 antibody restores functionality of HIV-specific CD8 T cells from HIV patients. Up-regulation of PD-1 in HIV patients also leads to T cell dysfunction (2). Although a small proportion of cells express both TIM-3 and PD-1, in the majority of cells, TIM-3 expression is distinct from PD-1, suggesting these proteins define separate populations of dysfunctional T cells in HIV patients. (B) In autoimmune diseases, autoreactive T cells upon activation and expansion down-regulate TIM-3 expression, leading to progressive uncontrolled growth and expansion of autoreactive T cells. Whether down-regulation of TIM-3 is mediated by genetic factors or by T cell activation signals in autoimmune disease is not known.