INVOLVEMENT OF LAMININ AND ITS RECEPTOR IN ABROGATION OF HEART GRAFT-REJECTION BY AUTOREACTIVE T-CELLS FROM TRYPANOSOMA CRUZI-INFECTED MICE

Extracellular matrix ligands and receptors have been identified as det ermining in vivo lymphocyte positioning and activation, including effe ctor functions in alloreactive responses. Herein we evaluated the invo lvement of laminin and its receptor, the very late antigen 6 (VLA-6) i ntegrin, in CD4(+) T cell-dependent autoreactivity, using a transplant ation model for the autoimmune myocarditis occurring in mice chronical ly infected with Trypanosoma cruzi. Previous work showed that syngenei c mouse hearts grafted in the ears of chronic chagasic recipients were rejected through a CD4(+) T cell-dependent mechanism. Rejection also occurred when cells from chagasic animals were transferred adjacent to hearts transplanted into naive recipients. Here, we observed the form ation of a thick laminin network during rejection, with donor-derived CD4(+) T cells concentrated in the laminin-rich areas. Most importantl y, anti-laminin as well as anti-laminin receptor Ab inhibited the reje ction of syngeneic hearts by T cells from chagasic animals. Our result s suggest that interaction of the VLA-B molecule with laminin is invol ved in triggering the antimyocardial autoreactive process by driving t he influx of CD4(+) T cells to the heart. They also support the concep t that an Ag-specific T cell response, even an autoreactive one, can b e modulated by in vivo interactions involving extracellular matrix lig ands and receptors. In this regard, our study represents, to our knowl edge, the first in vivo evidence for laminin-mediated T cell echotaxis , with simultaneous experimental demonstration of ligand and receptor involvement. Lastly, our findings indicate that treatment with anti-VL A-6 Abs can be effective in suppressing autoimmune disease activity.