Background:Our recent work demonstrated that laminins α4β1γ1 and α5β1γ1, components of the lymph node (LN) stroma, are differentially regulated. Tolerance is associated with relatively higher laminin α4 expression, while immunity is associated with laminin α5 upregulation. These differences resulted in altered regulation of alloreactive T cell and antigen-presenting cell trafficking within and extravasation through high endothelial venules. Here, we tested the hypothesis that laminins directly regulate CD4 T cell activation and proliferation.

Methods:CD4 T cells from C57BL/6 mice were activated with anti-CD3 with or without laminin α4 and/or α5. The laminin α5 receptor was blocked with anti-α6 integrin mAb. After 3 days of culture, T cell proliferation and CD69, CD25, CD44 and CD62L expression were determined by flow cytometry. For in vivo experiments, TCR Tg CD4 cells from TEa mice that recognize donor I-E^d presented by recipient I-A^b were transferred, with or without anti-α6 integrin mAb, into C57BL/6 mice that had received BALB/c donor-specific splenocytes (DST) or CFA/Eα peptide emulsion; and T cell proliferation and activation were analyzed. For allografting, C57BL/6 mice received heterotopic cardiac transplants from BALB/c mice and were treated with anti-α6 Ab.

Results:Addition of laminin α4β1γ1 to anti-CD3 stimulated cultures reduced CD4 T cell proliferation and activation. In contrast, addition of laminin α5β1γ1 increased proliferation and activation marker expression by up to 8-fold, and upregulated phosphorylation of AKT and ERK1/2. Addition of anti-α6 integrin blocking mAb abrogated the stimulatory effect, demonstrating that α6 integrin is the main T cell receptor for laminin α5. In vivo, systemic blockade of α6 integrin resulted in decreased proliferation and activation of alloantigen specific CD4 T cells in the LNs of DST or CFA/Ea peptide treated mice. The treatment of cardiac allograft recipient mice with anti-α6 integrin resulted in a significant prolongation of graft survival.

Conclusions:These results demonstrate that the laminin trimers α4β1γ1 and α5β1γ1 are co-inhibitory and co-stimulatory ligands, respectively, for CD4 T cells. Laminin α5β1γ1 is recognized by the integrin α6 expressed by T cells. These data confirmed the immunogenic role of this laminin-specific receptor and suggested a co-stimulatory role for laminin α5β1γ1 in vivo. These findings demonstrate that laminins are not only passive LN structural molecules, but act as molecular switches for tolerance and immunity by directly influencing T cell activation.

CITATION INFORMATION: Simon T, Bromberg J. Lymph Node Stromal Laminins Differentially Regulate T Cell Activation. Am J Transplant. 2017;17 (suppl 3).

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