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

ABSTRACT: BACKGROUND:Stromal laminins ?4 and ?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 ?4 and/or ?5. Laminin ?5 receptors were blocked with anti-?6 integrin or anti-?-dystroglycan (?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 ?4 and ?5 were differentially regulated. Immunity was associated with decreased laminin ?4:?5 ratio, while tolerance was associated with an increased ratio. Laminin ?4 inhibited CD4+ T-cell proliferation and Th1, Th2, and Th17 polarization but favored Treg induction. Laminin ?5 favored T-cell activation and Th1, Th2, and Th17 polarization and inhibited Treg. Laminin ?5 was recognized by T cell integrin ?6 and is important for activation and inhibition of Treg. Laminin ?5 was also recognized by T cell ?-DG and required for Th17 differentiation. Anti-?6 integrin or anti-DG prolonged allograft survival. CONCLUSIONS:Laminins ?4 and ?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.

SUBMITTER: Simon T

PROVIDER: S-EPMC6768765 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Simon Thomas T Li Lushen L Wagner Chelsea C Zhang Tianshu T Saxena Vikas V Brinkman C Colin CC Tostanoski Lisa H LH Ostrand-Rosenberg Suzanne S Jewell Chris C Shea-Donohue Terez T Hippen Keli K Blazar Bruce B Abdi Reza R Bromberg Jonathan S JS

Transplantation 20191001 10

<h4>Background</h4>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.<h4>Methods</h4>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) monoclona ...[more]

PMID: 31343575

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Project description:BACKGROUND:Systemic autoimmunity can be present years before clinical onset of rheumatoid arthritis (RA). Adaptive immunity is initiated in lymphoid tissue where lymph node stromal cells (LNSCs) regulate immune responses through their intimate connection with leucocytes. We postulate that malfunctioning of LNSCs creates a microenvironment in which normal immune responses are not properly controlled, possibly leading to autoimmune disease. In this study we established an experimental model for studying the functional capacities of human LNSCs during RA development. METHODS:Twenty-four patients with RA, 23 individuals positive for autoantibodies but without clinical disease (RA risk group) and 14 seronegative healthy control subjects underwent ultrasound-guided inguinal lymph node (LN) biopsy. Human LNSCs were isolated and expanded in vitro for functional analyses. In analogous co-cultures consisting of LNSCs and peripheral blood mononuclear cells, ?CD3/?CD28-induced T-cell proliferation was measured using carboxyfluorescein diacetate succinimidyl ester dilution. RESULTS:Fibroblast-like cells expanded from the LN biopsy comprised of fibroblastic reticular cells (gp38+CD31-) and double-negative (gp38-CD31-) cells. Cultured LNSCs stably expressed characteristic adhesion molecules and cytokines. Basal expression of C-X-C motif chemokine ligand 12 (CXCL12) was lower in LNSCs from RA risk individuals than in those from healthy control subjects. Key LN chemokines C-C motif chemokine ligand (CCL19), CCL21 and CXCL13 were induced in LNSCs upon stimulation with tumour necrosis factor-? and lymphotoxin ?1?2, but to a lesser extent in LNSCs from patients with RA. The effect of human LNSCs on T-cell proliferation was ratio-dependent and altered in RA LNSCs. CONCLUSIONS:Overall, we developed an experimental model to facilitate research on the role of LNSCs during the earliest phases of RA. Using this innovative model, we show, for the first time to our knowledge, that the LN stromal environment is changed during the earliest phases of RA, probably contributing to deregulated immune responses early in disease pathogenesis.

Dataset Information

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

Publications

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

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