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

Transplantation. 2019 Oct;103(10):2075-2089. doi:10.1097/TP.0000000000002774
Thomas Simon 1 , Lushen Li 1 , Chelsea Wagner 1 , Tianshu Zhang 2 , Vikas Saxena 1 , C Colin Brinkman 1 , Lisa H Tostanoski 3 , Suzanne Ostrand-Rosenberg 4 , Chris Jewell 3 , Terez Shea-Donohue 5 , Keli Hippen 6 , Bruce Blazar 6 , Reza Abdi 7 , Jonathan S Bromberg 1
Thomas Simon 1 , Lushen Li 1 , Chelsea Wagner 1 , Tianshu Zhang 2 , Vikas Saxena 1 , C Colin Brinkman 1 , Lisa H Tostanoski 3 , Suzanne Ostrand-Rosenberg 4 , Chris Jewell 3 , Terez Shea-Donohue 5 , Keli Hippen 6 , Bruce Blazar 6 , Reza Abdi 7 , Jonathan S Bromberg 1
+ et al

[No authors listed]

Author information
  • 1 Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD.
  • 2 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.
  • 3 Fischell Department of Bioengineering, University of Maryland, College Park, MD.
  • 4 Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD.
  • 5 Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD.
  • 6 The Center for Immunology, University of Minnesota Medical School, Minneapolis, MN.
  • 7 Transplantation Research Center and Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

摘要


BACKGROUND:Stromal laminins α4 and α5 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 α4 and/or α5. Laminin α5 receptors were blocked with anti-α6 integrin or anti-α-dystroglycan (αDG) 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 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 is important for activation and inhibition of Treg. Laminin α5 was also recognized by T cell α-DG and required for Th17 differentiation. Anti-α6 integrin or anti-DG prolonged allograft survival. CONCLUSIONS:Laminins α4 and α5 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.