Much is known about the mechanisms of tolerance, such as anergy, apoptosis, and regulatory T cells (Treg). However, it is difficult to induce and maintain robust tolerance that is resistant to external perturbations. This suggests other important mechanisms that determine tolerance remain to be elucidated. Foxp3+ regulatory suppressive CD4+ T cells (Treg) are integral for establishing and maintaining tolerance to autoantigens and alloantigens. Treg share many characteristics with nave and activated conventional, CD4+ T cells (Tconv). However, since Treg and Tconv responses are not precisely aligned, these observations do not define the mechanisms of how Treg are directed, or identify why their function is predominantly limited to the right place at the right time. How Treg function is geographically and kinetically channeled in ways distinct from Tconv function remains elusive. In prior work we demonstrated that specific trafficking behavior is required for Treg to fully function and suppress allograft rejection: they must sequentially migrate from blood through microvascular endothelium into the tissue, and then from tissue through afferent lymphatics into the draining lymph nodes (dLN). If any part of this sequence is interrupted, Treg fail to become activated and suppress tissue and LN responses of Tconv and dendritic cell (DC). Thus, a major characteristic of Treg physiology, and a step apparently not required for Tconv and effector function, is afferent lymphatic migration. Our new investigations now demonstrate both natural thymus derived Treg (nTreg) and peripherally induced Treg (iTreg) express elevated lymphotoxin alpha and beta (LT??). Treg use LT?? to migrate across afferent lymphatic endothelial cells (LEC). Treg LT?? binds to the LEC LT beta receptor (LT?R) for transendothelial migration. Treg-LEC engagement induces cytoskeletal changes in the LEC and rapid outgrowth of LEC lamellipodia that engage the Treg. The LT??-LT?R interaction depends non-canonical NF?B-inducing kinase (NIK) signaling via the LT?R in LEC, but does not depend on the classical NF?B or JNK pathways. Transendothelial migration also depends on LEC VCAM engagement and rearrangements of vinculin and filamentous actin. These highly specialized interactions do not occur with Tconv, and do not occur with blood vascular endothelial cells (BEC). Thus Treg-LEC interactions are distinct from those involving Tconv-LEC, Treg-BEC, and Tconv-BEC. Our data demonstrate a novel form of T cell migration used only by Treg in tissues; one that we believe serves an essential role in their suppressive physiology, and identifies a unique therapeutic opportunity for modulating suppression. These observations have led us to propose the hypotheses that: 1.) LT-dependent afferent lymphatic migration is required for Treg to regulate immunity and inflammation peripherally in tissues; 2.) LT-dependent afferent lymphatic migration is required for Treg to regulate immunity and inflammation centrally in dLN secondary lymphoid organs; and 3.) LT??-LT?R-dependent interactions determine immune responses and functions of both Treg and LEC.
Achieving tolerance remains the most important goal in transplantation. The significance of the current proposal is that it will define for the first timethe function and mechanisms of lymphotoxins and how they regulated the migration and function of suppressive regulatory T cells. The findings from these investigations will have general applicability to other areas of immunology such as infection, vaccination, and autoimmunity.
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