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 3

Antigen-specific CD4+ T cells home to the cortical ridge following the induction of tolerance.

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Antigen-specific CD4+ T cells home to the cortical ridge following the i...
CD4+ TEa cells were labeled with CFSE and transferred to naive, immune (DST), or tolerized (DST + anti-CD40L) C57BL/6 mice. Recipients were euthanized 4 hours (B) or 24 hours (C) after cell transfer. LNs were harvested, and 5-μm cryosections were analyzed for cell migration and location by fluorescent immunohistochemistry of structures identified by ER-TR7+ stromal fibers and PNAd+ HEVs. Cells were categorized as intraendothelial, within endothelium/basement membrane, within basement membrane, outside HEV, within cortical ridge, and beyond cortical ridge. (A) Representative fluorescent confocal immunohistochemistry of antigen-specific CD4+ T cells. Arrows denote cells present in designated locations. Original magnification, ×1,000 (leftmost 3 panels), ×100 (right panel). (B and C) Quantitation of T cell distribution 4 hours after cell transfer from ×1,000 images (B) and 24 hours after cell transfer from ×100 images (C). Data presented as mean ± SEM. n = 3–5 mice per treatment; 1–4 LNs per mouse; *P < 0.05, **P < 0.005, ***P < 0.0005.