Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 124, Issue 5, Pages 2204-2218Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI73683
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Funding
- NIH [R01-A1062765, R56-AI72039, T32-AI078892, HL007698]
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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 alpha 4 to laminin alpha 5 was greater in domains within tolerant LNs, compared with immune LNs, and blocking laminin alpha 4 function or inducing laminin alpha 5 overexpression disrupted T cell and DC localization and transmigration through tolerant LNs. Furthermore, reducing alpha 4 laminin circumvented tolerance induction and induced cardiac allograft inflammation and rejection in murine models. This work identifies laminins as potential targets for immune modulation.
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