The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model
Takuya Ueno, Antje Habicht, Michael R. Clarkson, Monica J. Albin, Kazuhiro Yamaura, Olaf Boenisch, Joyce Popoola, Ying Wang, Hideo Yagita, Hisaya Akiba, M. Javeed Ansari, Jaeseok Yang, Laurence A. Turka, David M. Rothstein, Robert F. Padera, Nader Najafian, Mohamed H. Sayegh
Takuya Ueno, Antje Habicht, Michael R. Clarkson, Monica J. Albin, Kazuhiro Yamaura, Olaf Boenisch, Joyce Popoola, Ying Wang, Hideo Yagita, Hisaya Akiba, M. Javeed Ansari, Jaeseok Yang, Laurence A. Turka, David M. Rothstein, Robert F. Padera, Nader Najafian, Mohamed H. Sayegh
View: Text | PDF
Research Article

The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model

Abstract

T cell Ig mucin 1 (TIM-1) plays an important role in regulating immune responses in autoimmune and asthma models, and it is expressed on both Th1 and Th2 cells. Using an antagonistic TIM-1–specific antibody, we studied the role of TIM-1 in alloimmunity. A short course of TIM-1–specific antibody monotherapy prolonged survival of fully MHC-mismatched vascularized mouse cardiac allografts. This prolongation was associated with inhibition of alloreactive Th1 responses and preservation of Th2 responses. TIM-1–specific antibody treatment was more effective in Th1-type cytokine–deficient Stat4–/– recipients as compared with Th2-type cytokine–deficient Stat6–/– recipients. Subtherapeutic doses of rapamycin plus TIM-1–specific antibody resulted in allograft acceptance and prevented the development of chronic allograft vasculopathy. Allograft survival via this treatment was accompanied by a Th1- to Th2-type cytokine switch. Depletion of natural Tregs abrogated the graft-protecting effect of the TIM-1–specific antibody. Importantly, CD4+CD25+ Tregs obtained from long-term survivors had enhanced regulatory activity as compared with naive CD4+CD25+ Tregs. Consistent with this, TIM-1–specific antibody treatment both preserved Tregs and prevented the expansion of alloreactive effector Th1 cells in an alloreactive TCR transgenic adoptive transfer model. These studies define previously unknown functions of TIM-1 in regulating alloimmune responses in vivo and may provide a novel approach to promoting transplantation tolerance.

Authors

Takuya Ueno, Antje Habicht, Michael R. Clarkson, Monica J. Albin, Kazuhiro Yamaura, Olaf Boenisch, Joyce Popoola, Ying Wang, Hideo Yagita, Hisaya Akiba, M. Javeed Ansari, Jaeseok Yang, Laurence A. Turka, David M. Rothstein, Robert F. Padera, Nader Najafian, Mohamed H. Sayegh

×

Figure 8

Anti–TIM-1 does not convert naive CD4+CD25– to CD4+CD25+Foxp3+ T cells.

Options: View larger image (or click on image) Download as PowerPoint
Anti–TIM-1 inhibits the expansion of ABM TCR-Tg T cells, tipping the bal...
(A) Freshly isolated ABM TCR-Tg CD4+ CD25– T cells were stimulated with allospecific irradiated bm12 splenocytes in the absence and presence of TGF-β (3 ng/ml) and increasing concentrations of anti–TIM-1 mAb (1 μg/ml, 10 μg/ml, and 100 μg/ml) for 4 days. Viable Vα2.1+Vβ8.1+ cells were stained for the expression of CD25 and Foxp3. TGF-β induced the conversion of CD4+CD25– to CD4+CD25+Foxp3+ T cells; however, the addition of anti–TIM-1 (here shown for the concentration of 100 μg/ml) had no additional effect. The dot plots shown are representative of 3 separate experiments. (B) Following adoptive transfer of 2 × 106 CD4+CD25– ABM TCR-Tg T cells into nude B6 mice, recipients were transplanted with bm12 skin grafts and received mAbs against TIM-1. Cells from the dLNs and the spleen were again harvested after 7 days. The frequency Foxp3+ ABM TCR-Tg T cells was determined as described in Methods. Anti–TIM-1 mAb did not enhance the frequency of CD4+CD25+FoxP3+ ABM TCR-Tg T cells present in the dLNs when only ABM TCR-Tg CD4+CD25– cells were transferred. Similarly, no effect was observed in the spleen.