Abstract
Engagement of T-cell immunoglobulin mucin (Tim)-1 on T cells with its ligand, Tim-4, on antigen presenting cells delivers positive costimulatory signals to T cells. However, the molecular mechanisms for Tim-1-mediated regulation of T-cell activation and differentiation are relatively poorly understood. Here we investigated the role of Tim-1 in T-cell responses and allograft rejection using recombinant human Tim-1 extracellular domain and IgG1-Fc fusion proteins (Tim-1-Fc). In vitro assays confirmed that Tim-1-Fc selectively binds to CD4+ effector T cells, but not dendritic cells or natural regulatory T cells (nTregs). Tim-1-Fc was able to inhibit the responses of purified CD4+ T cells that do not express Tim-4 to stimulation by anti-CD3/CD28 mAbs, and this inhibition was associated with reduced AKT and ERK1/2 phosphorylation, but it had no influence on nTregs. Moreover, Tim-1-Fc inhibited the proliferation of CD4+ T cells stimulated by allogeneic dendritic cells. Treatment of recipient mice with Tim-1-Fc significantly prolonged cardiac allograft survival in a fully MHC-mismatched strain combination, which was associated with impaired Th1 response and preserved Th2 and nTregs function. Importantly, the frequency of Foxp3+ cells in splenic CD4+ T cells was increased, thus shifting the balance toward regulators, even though Tim-1-Fc did not induce Foxp3 expression in CD4+CD25− T cells directly. These results indicate that Tim-1-Fc can inhibit T-cell responses through an unknown Tim-1 binding partner on T cells, and it is a promising immunosuppressive agent for preventing allograft rejection.
Highlights
T-cell immunoglobulin mucin (Tim) proteins represent a newly discovered family of molecules that play critical roles in regulation of T helper cell 1 (Th1) and Th2 immune responses
Treatment with Tim-1-Fc successfully prolonged allograft survival in a MHC-mismatched murine cardiac transplantation model, this was associated with impaired Th1 response and preserved Th2 and natural regulatory T cells (nTregs) function
Upon stimulation with anti-CD3 and anti-CD28 mAbs for 72 h, CD4+CD252 T cells showed a distinct peak shift compared with the Human IgG1 (hIgG1) control and this binding could not be abolished by antiTim-4 mAb (Figure 1C)
Summary
T-cell immunoglobulin mucin (Tim) proteins represent a newly discovered family of molecules that play critical roles in regulation of T helper cell 1 (Th1) and Th2 immune responses. Tim-4-Ig was demonstrated to inhibit naive mouse CD4+ T-cell activation through a ligand other than Tim-1, and such an inhibitory effect of Tim-4-Ig was specific to naive T cells, and the effect disappeared in pre-activated T cells[10]. This suggests the possibility that the opposite effect of Tim-4-Ig on T-cell activation observed in the previous study[4] could be resulted from engagement with different receptors on T cells. Further elucidation of the role of Tim-1 in regulating T-cell responses is highly important for developing novel therapeutic strategies targeting Tim-1 for the treatment of autoimmune diseases and allograft rejection
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