Foxp3+ regulatory T cells (Treg) are required for transplant tolerance, however, where and when they are induced and activated remains uncertain. During costimulatory blockade induced tolerization, nave T cells migrate to the lymph node (LN), but not the spleen, where they are stimulated by alloantigen presenting plasmacytoid dendritic cells (pDC), and differentiate into induced Treg (iTreg). We have identified the adhesion and chemokine molecules which orchestrate tolerance by directing the localized accumulation of Treg in the cortical ridge (CR) of the LN where the high endothelial venules (HEV) are present. HEV are the main gatekeeper of T cell trafficking. Overall, naive T cells migrate to the CR and become iTreg, while T cells that become anergic or apoptotic migrate to other regions of the LN. Thus, a unique LN domain is required for the generation and activity of tolerogenic iTreg. The overall hypothesis is that this domain is required for tolerance, and the goal is to define the key events that regulate this structure and can be leveraged for tolerization. In this specialized LN domain the stromal fiber laminin ?4:?5 ratios determine the response to alloantigen. Laminins surrounding the HEV and CR act as gatekeepers for T cell fate by directly instructing T cell entry, conversion to iTreg, and the fate of later T cell cohorts, with a high laminin ?4:?5 ratio favoring tolerance. Laminin ?4 (termed 411 for ??? chains) promotes CD4 and CD8 T cell motility and transendothelial and interstitial migration into the HEV and CR, promotes Foxp3 expression and iTreg maturation, and inhibits effector T cell differentiation. In contrast, laminin ?5 (or 511) inhibits migration into HEV, yet costimulates T cell proliferation and inflammatory Th17. T cells recognize laminin ?5 using both integrin ?6 and ?-dystroglycan (?DG) receptors, and ?DG-laminin ?5 specifically induces Th17. Antibodies to these receptors prolong graft survival and enhance iTreg migration to the CR. We generalized these concepts in other models (colitis, tumor immunity, chronic rejection, vaccination), and in each case immunity correlated with decreased laminin ?4:?5 ratios, while tolerance required an increased ratio. Altogether, our new data indicate that stromal cells regulate the LN laminin ?4:?5 ratio and control the fate of the immune response to inflammation and immunity (low ratio) or to suppression and tolerance (high ratio). Our specific hypothesis is that LN stromal cells integrate immune cues and thus regulate laminin structures, and this integration is a final common pathway that channels the immune response and allograft outcomes. Thus, remodeling of laminins is a facet of innate immunity whereby immune cues stimulate stromal cells (FRC, LEC, BEC) to modify LN structure, which subsequently determines adaptive immunity. The corollaries are: 1) laminins regulate the response to inflammation and immunity, which results in pro- inflammatory LN structures or even the pathologic response of immunologic scarring; and 2) laminins regulate the response to suppression and tolerance and result in homeostatic and pro-tolerogenic LN structures.
Achieving tolerance remains the most important goal in transplantation. The significance of the current proposal is that it will define the function and mechanisms of specialized stromal cells and stromal structures in the lymph node that determine transplantation tolerance, and how they determine the choice between immunity versus tolerance. The findings from these investigations will have general applicability to other areas of immunology such as infection, vaccination, and autoimmunity.
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