Date: Tuesday, June 4, 2019
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
*Purpose: Differential expression of lymph node (LN) stromal laminins α5β1γ1 (511) and α4β1γ1 (411) is associated with tolerance and immunity, respectively. We investigated the hypothesis that laminins directly regulate T cell migration and the response to allografts.
*Methods: CD4 T cell migration on laminin coated surfaces was measured with real-time live imaging. Transwell assays were conducted using Boyden chambers coated with blood endothelial cell (BEC) monolayers and a CCL21 chemokine gradient. In vitro flow with shear force was performed using the BioFlux system. C57BL/6 (WT) mice and Pdgfrb-Cre+/-x laminin α5flox/flox(KO) mice, lacking LN laminin α5, received cardiac transplants from BALB/c donors. Recipients or T cells were treated with blocking mAbs against the laminin 511 receptors α6 integrin or α-dystroglycan.
*Results: Laminin 411 promoted while laminin 511 inhibited CD4 T cell migration. Using transendothelial migration models, various T cell subsets including naïve CD4, T memory, T effector cells, natural and induced Tregs, and CD8 T cells were analyzed. All subsets behaved similarly: laminin 411 promoted while laminin 511 inhibited their transmigration efficiency across BEC monolayers toward CCL21, and blocking α6 integrin or α-dystroglycan inhibited the effect of laminin 511.Modeling in vivo blood vessel laminar flow showed that laminin 411 and 511 also had migration enhancing and inhibitory effects for both naïve CD4 and iTreg during conditions of shear stress, with laminin α5 interacting with both α6 integrin and α-dystroglycan receptors. After pretreating with mAbs to α-dystroglycan, naïve CD4 T cells and iTreg entered LN more efficiently through the HEV compared to the control group. In tacrolimus treated recipients, KO mice had significantly prolonged allograft survival than WT recipients (mean survival time (MST) 89 vs 27.5 days, p<.002). KO mice treated with a single dose of anti-CD40L had a trend for increased allograft survival compared to WT mice (MST 155 vs 91 days, p= 0.07).
*Conclusions: Laminin 411 enhanced T cell dynamics and promoted T cell migration, while laminin 511 displayed the opposite effects. Various T cell subsets responded similarly in a variety of 2- and 3-dimensional transendothelial migration models, and T cells recognized laminin α5 via both α6 integrin and α-dystroglycan. Laminin α5 deficient mice have a tolerant LN niche which facilitates T cell entry into LN and prolongs allograft survival, suggesting laminins as targets for inducing transplant tolerance.
To cite this abstract in AMA style:Li L, Shirkey M, Piao W, Xiong Y, Saxena V, Zhang T, Cerel BM, Paluskievicz C, Bromberg JS. Laminin Dependent T Cell Migration Determines Allograft Survival [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/laminin-dependent-t-cell-migration-determines-allograft-survival/. Accessed June 20, 2021.
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