*Purpose: Laminins are a family of heterotrimeric glycoproteins, and lymph node (LN) stromal laminins α4 and α5 modulate suppression and immunity, respectively. We created laminin α5 conditional knock out mice to test the hypothesis that laminin α5 depletion in LN stromal cells will impair alloimmunity and enhance cardiac allograft survival.

*Methods: Pdgfrb-Cre^+/- x laminin α5^flox/flox(KO) mice have laminin α5 gene deficiency of fibroblast reticular cells (FRC), lymphatic endothelial cells (LEC) and blood endothelial cells (BEC). Naïve CD4 T cell and induced regulatory T cell (iTreg) entry and distribution to the LN were evaluated through immunohistochemistry. C57BL/6 (WT) and KO micelacking LN laminin α5 received cardiac transplants from BALB/c donors. Blocking antibodies to the laminin α5 receptors, α6 integrin or α-dystroglycan, were administered to allograft recipients.

*Results: In the LNs of KO mice, lamininα5 was completely depleted in FRC and partially in BEC and LEC. In KO mice, the chemokines CXCL12 and CCL21 were specifically increased aroundthe cortical ridge and high endothelial venules (HEV), respectively, but with no differences in CCL19, CXCL9, or CXCL10. Adoptively transferred naïve CD4 T cells and iTreg migrated more efficiently toward LN in KO mice compared to WT controls. The transferred cells mainly localized to the T cell zone, particularly around HEV, indicating that depletion of laminin α5 facilitated the trafficking of CD4 T cells and Treg to the T cell zone through HEV.Blocking the laminin α5 receptor α-dystroglycanfacilitated naïve CD4 T cell and iTreg entry to LN through HEV compared to the control group. As compared to the isotype control group, blocking α-dystroglycan along with anti-CD40L administration prolonged graft survival (mean survival time (MST) 65 vs 154 days, p<0.002); and blocking the other laminin α5 receptor, α6 integrin, along with administration of anti-CD40L also dramatically prolonged allograft survival (MST 53 vs 167 days, p<0.002).

*Conclusions: Laminin α5 contributes to LN structure, and depletion of laminin α5 resulted in increasedchemokines in T cell zone and improved Treg entry and cortical ridge distribution in LN. T cells recognize laminin α5 through α6 integrin and α-dystroglycan, and blocking these receptors prolonged allograft survival. Manipulating laminin expression influences graft survival, suggesting laminins as targets for inducing transplant tolerance.

« Back to 2019 American Transplant Congress