Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*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+/-xLama5fl/fl, (KOfl) mice were adoptively transferred with CD4+ T cells and regulatory T cells (Treg) to analyze trafficking into LN. WT and KOfl 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 KOfl LN compared to WT. Transferred cells localized to the T cell zone of KOfl, 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 KOfl 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.
To cite this abstract in AMA style:Li L, Shirkey M, Piao W, Xiong Y, Saxena V, Zhang T, Paluskievicz C, Zhao J, Abdi R, Bromberg JS. Laminin Alpha5 Regulates T Cell Entry and Distribution in Lymph Nodes in Immunity [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/laminin-alpha5-regulates-t-cell-entry-and-distribution-in-lymph-nodes-in-immunity/. Accessed June 15, 2021.
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