*Purpose: Laminin α5 (Lama5) and α4 (Lama4), which are produced by lymph node (LN) stromal cells, influence CD4 T cell migration and stimulation. We hypothesized that laminins may regulate entry of T cells to LNs, thereby determining intranodal distribution and channeling alloimmunity under tolerant and immune conditions.

*Methods: The effects of Lama4 and Lama5 on mouse and human T cells were evaluated in static and shear flow transendothelial migration (TEM). Lama5 conditional knock out (KO) and Lama4 conditional KO mice, in which expression of these fibers was specifically deleted in fibroblastic reticular stromal cells, and littermate controls (WT) were adoptively transferred with CD4 T cells and regulatory T cells (Treg) to analyze their trafficking. WT and Lama5 KO recipients were treated with BALB/c donor-specific splenocytes (DST) and anti-CD40L mAb along with adoptive transfer of T cell receptor transgenic TEa CD4 T cells recognizing donor alloantigen.

*Results: Lama4 promoted but Lama5 inhibited TEM of various T cell subsets, including murine CD4 and CD8 naïve, memory and effector cells, Treg, and human activated CD4 T cells and Treg, in both static and shear stress flow conditions. Lama5 receptors on T cells were shown to be α6 integrin and α-dystroglycan (αDG) and blocking either with specific mAbs attenuated Lama5 inhibitory effects. Transferred CD4 T cells and Treg had enhanced entrance to Lama5 KO LNs and reduced entrance to Lama4 KO LNs. Transferred cells localized to the T cell zone, particularly the cortical ridge (CR) and around high endothelial venules (HEV), where Treg are induced. Blocking Lama5 receptors also promoted CD4 and Treg entry into the CR. Under both immune and tolerance conditions, more alloantigen specific T cells trafficked through Lama5 KO HEV and CR, demonstrating the inhibitory role of Lama5 for migration and Treg induction. After transplantation, depleting stromal Lama5 promoted TEa cell differentiation toward Foxp3+ Treg and suppressed the differentiation toward IL-17+ Th17 cells.

*Conclusions: Lama4 promoted human and murine T cell migration in homeostasis, immunity, and tolerant conditions. Lama5, through binding of the T cell adhesion receptors α6 integrin and αDG, inhibited T cell migration. Depleting stromal Lama5 promoted, while depleting Lama4 suppressed, CD4 T cell and Treg entrance into the LN, indicating laminins are efficient targets to modulate T cell trafficking and immunity to alter immune responses.

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