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The TIM gene family: emerging roles in immunity and disease

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Abstract

The search for cell-surface markers that can distinguish T helper 1 (TH1) cells from TH2 cells has led to the identification of a new gene family, encoding the T-cell immunoglobulin mucin (TIM) proteins, some of which are differentially expressed by TH1 and TH2 cells. The role of the TIM-family proteins in immune regulation is just beginning to emerge. Here, we describe the various TIM-family members in mice and humans, and discuss the genetic and functional evidence for their role in regulating autoimmune and allergic diseases.

Key Points

  • 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.

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Acknowledgements

We would like to thank D. Schlesinger and J. McIntire for their valuable help in computer searches and input to the manuscript.

Author information

Correspondence to Vijay K. Kuchroo.

Related links

Glossary

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

(EAE). An experimental model for the human disease multiple sclerosis (MS). Autoimmune disease is induced in experimental animals by immunization with myelin antigen or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

SYNTENY

Colinearity in the order of genes (or of other DNA sequences) in a chromosome region of two species.

RGD MOTIF

A peptide motif that consists of the amino acids arginine, glycine and aspartic acid, and is found in many ligands that bind integrins.

ALLERGEN-INDUCED AIRWAY HYPERREACTIVITY

(AHR). An experimental model of human allergic asthma in which mice are first sensitized to, then challenged with, allergen. This leads to airway hyperreactivity, a cardinal feature of asthma in humans.

EPISTASIS

An interaction between non-allelic genes, such that one gene masks, interferes with or enhances the expression of the other gene.

TC1 CELLS

CD8+ T cells that produce T helper 1 cytokines, particularly interferon-γ.

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Further reading

Figure 1: Schematic representation of TIM-protein structures.
Figure 2: Genomic organization of human and mouse TIM genes.
Figure 3: Dendrogram showing sequence similarity in the TIM gene family.
Figure 4: Possible mechanisms by which hepatitis A virus might reduce the development of atopic diseases.
Figure 5: Tim2–Sema4A interactions.
Figure 6: Hypothetical mechanisms by which the interaction between TIM3 and TIM3 ligand induces macrophage activation.