*Purpose: Lymph node (LN) stromal cell expressed laminin α4 (Lama4) and laminin α5 (Lama5) fibers are associated with tolerance and immunity, respectively. They regulate cell trafficking within the LN. We hypothesized that stromal Lama4 and Lama5 differentially regulate specific alloimmune responses.

*Methods: LN stromal Lama5 conditional KO and Lama4 conditional KO mice on a C57BL/6 background were established. Littermate control (WT) and Lama5 KO mice received BALB/c donor-specific splenocytes (DST), or DST plus anti-CD40L mAb for immune and tolerance induction, respectively. T cell receptor transgenic CD4 TEa cells recognizing alloantigen were adoptively transferred into recipients. TEa cell migration, distribution, activation, and differentiation were analyzed. BALB/c donor hearts were transplanted into Lama4, Lama5 KO and WT mice and graft survival measured.

*Results: Alloantigen specific TEa cell activation to CD44^hiCD69⁺ effector cells were lower in Lama5 KO LN compared to WT, indicating that depletion of Lama5 prevented T cell activation. Under tolerance conditions, activation induced cell death of TEa cells in LN was lower in Lama5 KO than WT, showing that inhibition of T cell activation preserved antigen specific T cells. Under both tolerance and immune conditions, TEa cell differentiation to Foxp3+ Treg and IL-17+ Th17 was altered, making the Foxp3:Th17 ratio higher in Lama5 KO than in WT. Low dose tacrolimus (2 mg/kg/d) treated Lama5 KO cardiac recipients had significantly prolonged allograft survival (mean survival time (MST) 89 days vs 27.5 days in WT, p<.002). Low dose anti-CD40L mAb treated Lama5 KO recipients also had prolonged allograft survival (MST 155 vs 91 days in WT, p=0.07). In contrast, tacrolimus treated Lama4 KO recipients had significantly shorter allograft survival (MST 11.5 days vs 18 days in WT, p<.002). Lama4 KO recipients receiving a single dose of anti-CD40L displayed a trend for decreased survival (MST 42.5 vs 60 days, p<0.01).

*Conclusions: Depleting stromal Lama5 suppressed T cell activation, and channeled alloantigen specific T cell differentiation from inflammatory to suppressive regulatory phenotypes. Depleting stromal Lama5 also promoted Treg induction and inhibited Th17 differentiation, creating a tolerogenic niche to enhance cardiac allograft survival. LN stromal Lama4 is necessary for allograft tolerance. Targeting laminins on LN stromal cells could be efficient to modulate adaptive immune responses.

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