Transplantation | 2019
Differential Regulation of T Cell Immunity and Tolerance by Stromal Laminin Expressed in the Lymph Node.
Abstract
BACKGROUND\nStromal laminins α4 and α5 are differentially regulated in transplant tolerance and immunity, respectively, resulting in altered T cell trafficking. We hypothesized laminins directly regulated T cell activation and polarization.\n\n\nMETHODS\nHuman and mouse CD4 T cells were activated in Th1, Th2, Th17 or Treg environments with/without laminin α4 and/or α5. Laminin α5 receptors were blocked with anti-α6 integrin or anti-α dystroglycan mAbs, and T cell polarization determined. TCR 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.\n\n\nRESULTS\nIn diverse models, laminins α4 and α5 were differentially regulated. Immunity was associated with decreased laminin α4:α5 ratio, while tolerance was associated with an increased ratio. Laminin α4 inhibited CD4+ T cell proliferation and Th1, Th2 and Th17 polarization, but favored Treg induction. Laminin α5 favored T cell activation and Th1, Th2, and Th17 polarization; and inhibited Treg. Laminin α5 was recognized by T cell integrin α6 and important for activation and for inhibition of Treg. Laminin α5 was also recognized by T cell α-dystroglycan and required for Th17 differentiation. Anti-α6 integrin or anti-α-dystroglycan prolonged allograft survival.\n\n\nCONCLUSIONS\nLaminins α4 and α5 are, respectively, co-inhibitory and co-stimulatory ligands for human and mouse CD4 T cells. Laminins and their receptors modulate immune responses by acting as one of the molecular switches for immunity or suppression.