*Purpose: Laminin α5 (Lama5) and α4 (Lama4) are lymph node (LN) stromal fibers whose expression ratio influences CD4+ T cell migration and stimulation. We hypothesized that Lama5 may regulate entry to LN of many other T cell subsets, thereby determining intranodal distribution and channeling alloimmunity under tolerant and stimulated conditions.

*Methods: The effects of Lama4 and Lama5 on mouse and human T cells were evaluated in transendothelial migration (TEM) models. In vitro shear force flow was performed with the BioFlux system. C57BL/6 wild type (WT) and stromal Lama5 conditional knockout, Pdgfrb-Cre^+/-xLama5^fl/fl, (KO^fl) mice were adoptively transferred with CD4+ T cells and regulatory T cells (Treg) to analyze trafficking into LN. WT and KO^fl recipients were treated with BALB/c donor-specific splenocytes (DST) and anti-CD40L mAb along with adoptive transfer of T cell receptor transgenic TEα CD4+ T cells recognizing donor alloantigen.

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

*Conclusions: Lama4 promoted human and murine T cell TEM in homeostasis, immunity, and tolerance. Lama5, through binding of the T cell α6 integrin and αDG receptors, inhibited T cell migration. Depleting stromal Lama5 promoted CD4+ T cell and Treg entrance into the LN, indicating Lama5 is an efficient target to modulate T cell trafficking and immunity to promote transplant acceptance.

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