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

Simon, Thomas PhD1,2; Li, Lushen PhD1,2; Wagner, Chelsea BA1,2; Zhang, Tianshu PhD1; Saxena, Vikas PhD1,2; Brinkman, C. Colin PhD1,2; Tostanoski, Lisa H. PhD3; Ostrand-Rosenberg, Suzanne PhD4; Jewell, Chris PhD3; Shea-Donohue, Terez PhD5; Hippen, Keli PhD6,7; Blazar, Bruce MD6,7; Abdi, Reza MD8; Bromberg, Jonathan S. MD, PhD1,2

doi: 10.1097/TP.0000000000002774
Original Basic Science–General
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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.

1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.

2 Center for Vascular and Inflammatory Diseases, 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 Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN.

7 The Center for Immunology, University of Minnesota Medical School, Minneapolis, MN.

8 Transplantation Research Center and Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

Received 26 November 2018. Revision received 17 February 2019.

Accepted 7 March 2019.

J.S.B. was supported by NIH Grants 1RO1AI114496 and 1RO1AI062765. The other authors declare no conflicts of interest.

J.S.B. and T.S. conceived the study, designed experiments, interpreted the data, and wrote the article. C.W., L.L., T.Z., V.S., C.C.B., L.H.T., S.O-R., C.J., T.S-D., and T.S. performed experiments. All the authors read and approved the final article. Correspondence and requests for materials should be addressed to J.S.B. or T.S.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Thomas Simon, PhD and Jonathan S. Bromberg, MD, PhD, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21202. (thomas.simon.lab@gmail.com; jbromberg@som.umaryland.edu).

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