The TIM gene family: emerging roles in immunity and disease

The T-cell immunoglobulin mucin (TIM) gene family is located on chromosome 11 in mice and 5q33 in humans. Genomic analysis has identified eight family members in mice and three in humans.TIM3 is not expressed by naive or activated T cells, but is expressed by T helper 1 (TH1) cells after several rounds of polarization in vitro.A locus encompassing the Tim family of genes on mouse chromosome 11 is linked to many autoimmune diseases in mice, and to airway hyperreactivity and TH2-cell pro-inflammatory responses. A syntenic region on human chromosome segment 5q33 is linked to asthma in humans.The locus that regulates mouse airway hyperreactivity includes the TIM family of genes. Tim1 and Tim3 are polymorphic between mouse airway hyperreactivity-susceptible and -resistant strains of mice.TIM1 was independently identified as a cellular receptor for hepatitis A virus. In humans, infection with hepatitis A virus seems to be associated with resistance to asthma and atopy indirectly. One possible explanation is that infection with hepatitis A virus might regulate the functions of TH2 cells by interacting with TIM1.Semaphorin 4A (sema4A), which is expressed by B cells, macrophages and dendritic cells is the ligand for Tim2. Blockade of sema4A inhibits clonal expansion of T cells and inhibits the development of autoimmune disease in mice.Engagement of TIM3 by TIM3-specific antibodies during an ongoing immune response, results in the activation and clonal expansion of macrophages, indicating that TIM3 might have a crucial role in regulating macrophages.Differential expression of TIM proteins by TH1 and TH2 cells might provide a useful target to regulate the functions of effector TH1 and TH2 cells.