TIMs: central regulators of immune responses

Negative Immune Regulator Tim-3 Is Overexpressed on T Cells in Hepatitis C Virus Infection and Its Blockade Rescues Dysfunctional CD4 + and CD8 + T Cells

“…Although the expression of PD-1 has been associated with T-cell exhaustion in HIV, HCV, and lymphocytic choriomeningitis virus (12,14), not all exhausted T cells express PD-1, supporting the concept that other inhibitory molecules are likely involved. The Tim family of genes, comprising eight members in mice and three members in humans, are located in regions associated with autoimmune and allergic diseases (9,23). Tim molecules are expressed on T cells, monocytes, and antigen-presenting cells, including macrophages and dendritic cells (9).…”

“…The Tim family of genes, comprising eight members in mice and three members in humans, are located in regions associated with autoimmune and allergic diseases (9,23). Tim molecules are expressed on T cells, monocytes, and antigen-presenting cells, including macrophages and dendritic cells (9). Tim-3 was initially found to be expressed on Th1 but not Th2 cells in mice (23), and reduction of Tim-3 expression in T cells using small interfering RNA or blocking antibodies was shown to increase secretion of the antiviral cytokine IFN-␥.…”

“…Recently, upregulation of programmed death 1 (PD-1) and downmodulation of CD127 (interleukin-7 receptor) have been linked to functional exhaustion of T cells in chronic HCV infection (5-7, 15, 21, 22). However, not all exhausted T cells express these phenotypic changes, and blockade of the PD-1/PD-L1 signaling pathway does not always reconstitute Th1/Tc1 cytokine production (4,5), indicating that other molecules may contribute to the exhaustion typically associated with chronic viral infections (9). One such molecule is Tim-3 (T-cell immunoglobulin and mucin domain-containing molecule 3), a membrane protein initially identified on terminally differentiated Th1 but not Th2 cells in mice (9).…”

“…However, not all exhausted T cells express these phenotypic changes, and blockade of the PD-1/PD-L1 signaling pathway does not always reconstitute Th1/Tc1 cytokine production (4,5), indicating that other molecules may contribute to the exhaustion typically associated with chronic viral infections (9). One such molecule is Tim-3 (T-cell immunoglobulin and mucin domain-containing molecule 3), a membrane protein initially identified on terminally differentiated Th1 but not Th2 cells in mice (9). A recent analysis of human immunodeficiency virus (HIV) infection demonstrates that Tim-3 is upregulated on both CD4 ϩ and CD8 ϩ T cells from patients with chronic infection relative to uninfected individuals and that virus-specific cells expressing high levels of Tim-3 secrete less IFN-␥ than do Tim-3-negative cells (10).…”

Emerging immune checkpoints for cancer therapy

“…nonetheless, a few other studies have suggested that TiM-3 also can promote a proinflammatory response and antitumor immune response [85][86][87]. TiM-3 is also characterized as a key regulator of the dysfunctional CD8  T-cell phenotype [73,88].…”