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

Thomas Simon, Lushen Li, Chelsea Wagner, Tianshu Zhang, Vikas Saxena, C. Colin Brinkman, Lisa H. Tostanoski, Suzanne Ostrand-Rosenberg, Chris Jewell, Terez Shea-Donohue, Keli Hippen, Bruce Blazar, Reza Abdi, Jonathan S. Bromberg

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2075-2089
Number of pages15
JournalTransplantation
Volume103
Issue number10
DOIs
StatePublished - Oct 1 2019

Fingerprint

Laminin
Immunity
Lymph Nodes
T-Lymphocytes
Dystroglycans
Laminin Receptors
Integrins
Isoantigens
Allografts
kalinin
Regulatory T-Lymphocytes
T-Cell Antigen Receptor
Inbred C57BL Mouse
Cell Movement
Cell Differentiation
Monoclonal Antibodies
Cell Proliferation
Ligands
Transplants

Cite this

Simon, T., Li, L., Wagner, C., Zhang, T., Saxena, V., Brinkman, C. C., ... Bromberg, J. S. (2019). Differential Regulation of T-cell Immunity and Tolerance by Stromal Laminin Expressed in the Lymph Node. Transplantation, 103(10), 2075-2089. https://doi.org/10.1097/TP.0000000000002774

Differential Regulation of T-cell Immunity and Tolerance by Stromal Laminin Expressed in the Lymph Node. / Simon, Thomas; Li, Lushen; Wagner, Chelsea; Zhang, Tianshu; Saxena, Vikas; Brinkman, C. Colin; Tostanoski, Lisa H.; Ostrand-Rosenberg, Suzanne; Jewell, Chris; Shea-Donohue, Terez; Hippen, Keli; Blazar, Bruce; Abdi, Reza; Bromberg, Jonathan S.

In: Transplantation, Vol. 103, No. 10, 01.10.2019, p. 2075-2089.

Research output: Contribution to journalArticle

Simon, T, Li, L, Wagner, C, Zhang, T, Saxena, V, Brinkman, CC, Tostanoski, LH, Ostrand-Rosenberg, S, Jewell, C, Shea-Donohue, T, Hippen, K, Blazar, B, Abdi, R & Bromberg, JS 2019, 'Differential Regulation of T-cell Immunity and Tolerance by Stromal Laminin Expressed in the Lymph Node', Transplantation, vol. 103, no. 10, pp. 2075-2089. https://doi.org/10.1097/TP.0000000000002774
Simon, Thomas ; Li, Lushen ; Wagner, Chelsea ; Zhang, Tianshu ; Saxena, Vikas ; Brinkman, C. Colin ; Tostanoski, Lisa H. ; Ostrand-Rosenberg, Suzanne ; Jewell, Chris ; Shea-Donohue, Terez ; Hippen, Keli ; Blazar, Bruce ; Abdi, Reza ; Bromberg, Jonathan S. / Differential Regulation of T-cell Immunity and Tolerance by Stromal Laminin Expressed in the Lymph Node. In: Transplantation. 2019 ; Vol. 103, No. 10. pp. 2075-2089.
@article{2606dfd1d23e4d68b83d3d2d620a328b,
title = "Differential Regulation of T-cell Immunity and Tolerance by Stromal Laminin Expressed in the Lymph Node",
abstract = "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.",
author = "Thomas Simon and Lushen Li and Chelsea Wagner and Tianshu Zhang and Vikas Saxena and Brinkman, {C. Colin} and Tostanoski, {Lisa H.} and Suzanne Ostrand-Rosenberg and Chris Jewell and Terez Shea-Donohue and Keli Hippen and Bruce Blazar and Reza Abdi and Bromberg, {Jonathan S.}",
year = "2019",
month = "10",
day = "1",
doi = "10.1097/TP.0000000000002774",
language = "English (US)",
volume = "103",
pages = "2075--2089",
journal = "Transplantation",
issn = "0041-1337",
publisher = "Lippincott Williams and Wilkins",
number = "10",

}

TY - JOUR

T1 - Differential Regulation of T-cell Immunity and Tolerance by Stromal Laminin Expressed in the Lymph Node

AU - Simon, Thomas

AU - Li, Lushen

AU - Wagner, Chelsea

AU - Zhang, Tianshu

AU - Saxena, Vikas

AU - Brinkman, C. Colin

AU - Tostanoski, Lisa H.

AU - Ostrand-Rosenberg, Suzanne

AU - Jewell, Chris

AU - Shea-Donohue, Terez

AU - Hippen, Keli

AU - Blazar, Bruce

AU - Abdi, Reza

AU - Bromberg, Jonathan S.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85072791663&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072791663&partnerID=8YFLogxK

U2 - 10.1097/TP.0000000000002774

DO - 10.1097/TP.0000000000002774

M3 - Article

C2 - 31343575

AN - SCOPUS:85072791663

VL - 103

SP - 2075

EP - 2089

JO - Transplantation

JF - Transplantation

SN - 0041-1337

IS - 10

ER -