Differential Regulation of T-cell Immunity and Tolerance by Stromal Laminin Expressed in the Lymph Node

Background. Stromal laminins alpha 4 and alpha 5 are differentially regulated in transplant tolerance and immunity, respectively, resulting in altered T-cell trafficking. We hypothesized that laminins directly regulated T-cell activation and polarization. Methods. Human and mouse CD4 T cells were activated in Th1, Th2, Th17, or regulatory T cell (Treg) environments with/without laminin alpha 4 and/or alpha 5. Laminin alpha 5 receptors were blocked with anti-alpha 6 integrin or anti-alpha-dystroglycan (alpha DG) monoclonal antibodies, and T-cell polarization was determined. T-cell receptor transgenic TEa CD4 cells that recognized donor alloantigen were transferred into C57BL/6 mice that received alloantigen or cardiac allografts. Laminin receptors were blocked, and TEa T-cell migration and differentiation were assessed. Laminin expression was measured in several models of immunity and tolerance. Results. In diverse models, laminins alpha 4 and alpha 5 were differentially regulated. Immunity was associated with decreased laminin alpha 4:alpha 5 ratio, while tolerance was associated with an increased ratio. Laminin alpha 4 inhibited CD4+ T-cell proliferation and Th1, Th2, and Th17 polarization but favored Treg induction. Laminin alpha 5 favored T-cell activation and Th1, Th2, and Th17 polarization and inhibited Treg. Laminin alpha 5 was recognized by T cell integrin alpha 6 and is important for activation and inhibition of Treg. Laminin alpha 5 was also recognized by T cell alpha-DG and required for Th17 differentiation. Anti-alpha 6 integrin or anti-DG prolonged allograft survival. Conclusions. Laminins alpha 4 and alpha 5 are coinhibitory and costimulatory ligands for human and mouse CD4 T cells, respectively. Laminins and their receptors modulate immune responses by acting as one of the molecular switches for immunity or suppression.