Background: Our prior studies demonstrated that tolerance and immunity are associated with differential expression of lymph node (LN) stromal laminins α4β1γ1 (411) and α5β1γ1 (511), respectively, which determine how alloreactive T cells enter high endothelial venules and traffic within LN. Here we tested whether laminins directly regulate CD4+ T cell receptor stimulation and migration, thereby determining immune responses and allograft survival.

Methods: CD4+ T cells isolated from C57BL/6 mice were activated with anti-CD3 +/- anti-CD28, cultured with laminins for 3 days, and evaluated for activation and proliferation. Migration of CD4 T cells on laminin coated surfaces was measured with real-time live imaging. C57BL/6 mice and laminin α5 floxed x Pdgfrb-Cre mice lacking laminin α5 expression in LN, received cardiac transplants from BALB/c donors. Recipients were treated with mAbs against the laminin 511 receptor α6 integrin.

Results: The proliferation and activation of anti-CD3 stimulated T cells were enhanced by laminin 511, but were inhibited by laminin 411. These effects were observed for a large range of dose and kinetic variables, demonstrating robust laminin effects. Laminin signals and T cell receptor and costimulatory signals must be presented together on the same surface for regulatory interactions to occur. Laminin 421 and laminin 521 displayed analogous effects, showing specificity for the α-chains. Laminin 411 enhanced while laminin 511 inhibited T cell migration. Blocking the laminin 511 receptor α6 integrin with specific mAb abrogated the stimulatory effect of laminin 511, as well as its influence on migration, indicating α6 integrin is the main receptor for laminin α5. Adding anti-α6 integrin to anti-CD40L mAb prolonged allograft survival (mean survival time 53 to 167 days (P=0.0018)). Laminin α5 deficient mice treated with anti-CD40L mAb also had a marked increase in allograft survival compared to wild type controls (109 vs 87 days).

Conclusions: Serving as co-inhibitory and co-stimulatory ligands, respectively, the laminin α4 and α5 chains regulate T cell receptor stimulation and migration. T cells recognize laminin α5 through α6 integrin, which acts as co-stimulatory receptors. mAbs targeting this receptor inhibited T cell responses and prolonged allograft survival. Laminins are not only structural scaffold molecules, but act as molecular switches for tolerance and immunity by directly regulating CD4+ T cell responses.

CITATION INFORMATION: Li L., Simon T., Piao W., Xiong Y., Saxena V., Zhang T., Wagner C., Bromberg J. Lymph Node Stromal Laminins Affect Graft Survival through Regulation of CD4 T Cell Proliferation and Migration Am J Transplant. 2017;17 (suppl 3).

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