Laminins affect T cell trafficking and allograft fate
Kristi J. Warren, … , Jonathan S. Bromberg, Bryna E. Burrell
Kristi J. Warren, … , Jonathan S. Bromberg, Bryna E. Burrell
Published April 1, 2014
Citation Information: J Clin Invest. 2014;124(5):2204-2218. https://doi.org/10.1172/JCI73683.
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Research Article Immunology

Laminins affect T cell trafficking and allograft fate

Abstract

Lymph nodes (LNs) are integral sites for the generation of immune tolerance, migration of CD4+ T cells, and induction of Tregs. Despite the importance of LNs in regulation of inflammatory responses, the LN-specific factors that regulate T cell migration and the precise LN structural domains in which differentiation occurs remain undefined. Using intravital and fluorescent microscopy, we found that alloreactive T cells traffic distinctly into the tolerant LN and colocalize in exclusive regions with alloantigen-presenting cells, a process required for Treg induction. Extracellular matrix proteins, including those of the laminin family, formed regions within the LN that were permissive for colocalization of alloantigen-presenting cells, alloreactive T cells, and Tregs. We identified unique expression patterns of laminin proteins in high endothelial venule basement membranes and the cortical ridge that correlated with alloantigen-specific immunity or immune tolerance. The ratio of laminin α4 to laminin α5 was greater in domains within tolerant LNs, compared with immune LNs, and blocking laminin α4 function or inducing laminin α5 overexpression disrupted T cell and DC localization and transmigration through tolerant LNs. Furthermore, reducing α4 laminin circumvented tolerance induction and induced cardiac allograft inflammation and rejection in murine models. This work identifies laminins as potential targets for immune modulation.

Authors

Kristi J. Warren, Daiki Iwami, Donald G. Harris, Jonathan S. Bromberg, Bryna E. Burrell

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Figure 10

Targeting the LN stromal fiber laminin α4 interferes with tolerance induction.

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Targeting the LN stromal fiber laminin α4 interferes with tolerance indu...
(A–F) Mice received DST + anti-CD40L (tolerant), DST only (immune), DST + anti-CD40L + MMPi (200 μg, i.v. [tolerant + MMPi]), or DST + anti-CD40L + anti–laminin α4 Ab (1 μg in the footpad [tolerant + anti–laminin α4]). Draining popliteal, inguinal, and para-aortic LN cryosections stained for indicated markers. (A) Total amount of laminin α5 associated with HEVs quantified. Controls are repeated from Figure 7D for statistical comparison (×1,000). (B) CFSE+ CD4+ TEa cells were transferred and their distribution quantified after 4 hours. Figure 3B control data are presented for statistical comparison. (C–F) Mice were euthanized 24 hours after treatment, and the percentage of CFSE+ TEa+ CD4+ T cells (C) and Foxp3+ (D), YAe+ (E), and PDCA-1+ (F) cells in the cortical ridge was determined. Data from Figure 6, B–D, for naive, immune, and tolerant mice are included for statistical comparison. (G and H) C57BL/6 mice received DST + anti-CD40L, DST + anti-CD40L + MMPi (200 μg, i.v., days –7, 0), or DST + anti–laminin α4 Ab (100 μg i.v., days –7, 0). Recipients received BALB/c heterotopic cardiac allografts on day 0. Graft function was monitored and survival recorded, and all mice were euthanized by day 40 (G). Grafts were analyzed by H&E staining (original magnification, ×600; H) and the parenchymal rejection/graft arterial disease (PR/GAD) score determined. Black arrows indicate areas of myocyte necrosis. Data presented as mean ± SEM (A–F and H) or percent survival (G). n = 3–7 mice per group. *P < 0.05, **P < 0.005, ***P < 0.0005.