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Differential Expression of Smad7 Transcripts Identifies the CD4⁺CD45RC^high Regulatory T Cells That Mediate Type V Collagen-Induced Tolerance to Lung Allografts ¹

Teruaki Mizobuchi^2,*,,, Kazuhiro Yasufuku^2,*,,, Yan Zheng, M. Azizul Haque, Kathleen M. Heidler^,, Kena Woods, Gerald N. Smith, Jr., Oscar W. Cummings, Takehiko Fujisawa^*, Janice S. Blum and David S. Wilkes^3,,

^* Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan; and Departments of Medicine, Microbiology and Immunology, and Pathology, Indiana University School of Medicine, Indianapolis, IN 46202

Regulatory T cells (Tregs) induced by oral tolerance may suppress immunity by production of TGF- that could also enhance Treg activity. However, all cells that are phenotypically Tregs in rats (CD4⁺CD45RC^high-RC^high) may not have regulatory function. Because Smad7 expression in T cells is associated with inflammation and autoimmunity, then lack of Smad7 may identify those cells that function as Tregs. We reported that feeding type V collagen (col(V)) to WKY rats (RT1^l) induces oral tolerance to lung allografts (F344-RT1^lvl) by T cells that produce TGF-. The purpose of the current study was to identify the Tregs that mediate col(V)-induced tolerance, and determine Smad7 expression in these cells. RC^high cells from tolerant rats were unresponsive to allogeneic stimulation and abrogated rejection after adoptive transfer. In contrast, CD4⁺CD45RC^low (RC^low) cells from tolerant rats and RC^high or RC^low cells from normal rats or untreated allograft recipients proliferated vigorously in response to donor Ags, and did not suppress rejection after adoptive transfer. TGF- enhanced proliferation in response to col(V) presented to tolerant RC^high, but not other cells. In contrast to other cells, only RC^high cells from tolerant rats did not express Smad7. Collectively, these data show that the Tregs that mediate col(V)-induced tolerance to lung allografts do not express SMAD7 and, therefore, are permissive to TGF--mediated signaling.

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