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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

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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 1

Distinct trafficking patterns of antigen-specific CD4+ T cells through HEVs following the induction of immunity and tolerance.

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Distinct trafficking patterns of antigen-specific CD4+ T cells through H...
CD4+ TEa cells and CD4+ OT-II cells were isolated, differentially labeled, and transferred at the time of DST with or without anti-CD40L injection to naive (untreated, n = 2), immune (DST, n = 3), or tolerized (DST + anti-CD40L, n = 3) C57BL/6 mice. Dextran revealed blood vessels. Total cells were categorized. Inguinal LNs imaged 20 to 180 minutes after cell transfer, on a single plane, for 800 frames (~12 minutes). (A) Representative images of inguinal LNs; original magnification, ×200. (B) Total number of cells detected 20 minutes after cell transfer quantified and set as 100% (horizontal dashed line). The percent increase or decrease of the total number was calculated for each time point. Bars represent the average cumulative percent change per group from 20 to 180 minutes after cell transfer. (C–F) Left column, line graphs: The number of cells circulating (C), rolling (D), rolling and tethered (E), or adherent (F) detected at 20 minutes after cell transfer set as 100%. Percent change calculated for each time point. Right column: Bars represent the average cumulative percent of total cells detected per group from 20 to 180 minutes after cell transfer. Data presented as mean SEM. Dependent on time: *P < 0.05, **P < 0.005, ***P < 0.0005. Dependent on treatment: ##P < 0.005, ###P < 0.0005.
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