A transmembrane protein has been identified, Tim-3, which is selectively expressed on the surface of TH1 cells and which may have a role in the induction of autoimmune disease.
Although twins can have very different personalities, telling them apart by looks alone can be difficult. Similarly, CD4+ T helper (TH) cells develop into effector TH1 and TH2 cells, which are characterized by their functions and cytokine profiles, but which are not easily distinguished using surface markers. Monney and colleagues now report in Nature the identification of a transmembrane protein, T-cell immunoglobulin- and mucin-domain-containing molecule (Tim-3), which is selectively expressed on the surface of TH1 cells and which may have a role in the induction of autoimmune disease.
To identify new TH1-specific cell-surface proteins the authors immunized rats with TH1-cell clones and from these animals generated and screened a panel of approximately 20,000 monoclonal antibodies. Two of the antibodies recognize a cell-surface protein present on TH1 cells but absent from TH2 cells. This protein was identified as Tim-3. Further experiments showed that Tim-3 is expressed on TH1 cells but not on naïve T cells, B cells, macrophages or dendritic cells. Tim-3 is not detectable on TH1 cells until cells have undergone three rounds of polarization with TH1-inducing cytokines. Expression at this late stage of T-cell development suggests that Tim-3 might not be involved in T-cell differentiation but could be important for the effector function of TH1 cells.
Monney and co-workers next investigated the effect of Tim-3 antibody administration on the development of experimental autoimmune encephalitis (EAE), a mouse model of multiple sclerosis, which is a TH1-mediated autoimmune disease of the central nervous system. Mice susceptible to EAE were immunized with an encephalitogenic protolipid protein peptide component of myelin, given anti-Tim-3 antibody and monitored for the development of EAE. Mice treated with anti-Tim-3 antibodies rapidly developed more severe disease than control mice, showing enhanced inflammation and demyelination. The demyelinating lesions in the anti-Tim-3 antibody-treated mice were filled with activated macrophages — one of the major cell types responsible for myelin destruction in EAE — which might explain the exacerbated disease in these animals.
The splenocytes of the mice treated with Tim-3 antibody showed higher basal proliferation and the spleens contained higher numbers of activated macrophages compared with control animals. The enhanced background proliferation in the Tim-3-treated mice was dependent on an interaction between anti-Tim-3-treated T cells and macrophages. These data indicate that engagement of Tim-3 during T-cell activation affects interactions between T cells and macrophages, and results in macrophage expansion and activation, which is probably responsible for the increased severity of this autoimmune disease.
The authors conclude that, because TH1 and TH2 cells cross-regulate each other's function, expression of Tim-3 on TH1 cells might, in addition to its role in development of autoimmunity, also have therapeutic implications for asthma and allergy.
Jenny Buckland
References
ORIGINAL RESEARCH PAPER Monney, L. et al. TH1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature415, 536–541 (2002). | Article | PubMed |
