Our lab’s major focus is on the mechanisms by which both immune and non-hematopoietic (tissue resident) cells maintain immune quiescence in both alloimmunity and autoimmunity. Our work has been instrumental in determining the cytokine ligands and receptors (including decoy non-signaling receptors) that maintain the eye’s immune and angiogenic privilege. Since these regulatory functions are susceptible to failure in states of high inflammation, we are also interested in (i) determining the mechanisms that lead to abrogation of the normal regulatory functions of immune cells and (ii) cytokine targeting strategies that can counter-balance these pathogenic mechanisms for restoring immune homeostasis. Our work has uncovered numerous mechanisms that regulate antigen-presenting/dendritic cell maturation and mobilization in the eye and lymphoid tissues, interactions between immune cells, including effector and regulatory T cells (Treg), with the ocular surface epithelium and vascular endothelium, and more recently Treg plasticity and regulatory breakdown in chronic inflammation. Our more recent program is focused on the effect of aging on the Treg-memory T cell balance.
Our lab was the first to (i) identify, phenotype and functionally characterize resident bone marrow-derived antigen-presenting cells (APC) of the cornea, (ii) identify novel mechanisms of corneal APC trafficking, (iii) define novel functional interactions between lymphatic endothelia and APC, (iv) identify selective topical cytokine and chemokine targeting to promote transplant survival by suppressing effector T cells, (v) define novel mechanisms employed by the corneal epithelium to maintain angiogenic privilege including the VEGFR-3 sink and PD-L1 mechanisms, and (vi) demonstrate the function of effector Th17 memory cells in pathogenesis of ocular surface autoimmunity Additionally, (vii) over the last decade we have conducted numerous studies to understand more clearly the contribution of Tregs to graft tolerance and the precise mechanisms that mediate this. Our lab has also been the first to identify the function of “Ex-Foxp3 Treg” (“ex-Treg”) in subverting allotolerance.
1. Regulatory T cells (Treg)- Our aim is to define the plasticity and functional range of Tregs in ocular transplantation and autoimmunity. We have identified multiple phenotypes of Tregs and defined the microenvironmental contexts in which Treg lose their immunoregulatory function. We have (i) identified Treg susceptibility to Th17-associated cytokines as underpinning chronic ocular surface autoimmunity, (ii) identified Treg plasticity as a key factor in loss of allotolerance, and have (iii) defined novel strategies to enhance Treg homing to the immune synapse for induction of graft tolerance.
2. Corneal Transplantation- Our group has been at the forefront of corneal transplantation immunology research, evaluating the pathways (direct vs. indirect) of host T cell sensitization in hosts with various degrees of risk for rejection. Our work was the first to demonstrate that the graft site microenvironment (in any form of transplant) can have a profound effect on the host pathway of allosensitization.
3. Angiogenesis and Lymphangiogenesis- Our lab has deciphered the differential contributions of blood vs. lymphatic vessels to antigen-specific immunity, establishing how blood and lymphatic vessels amplify the ‘efferent’ (effector) and ‘afferent’ (inductive or sensitization) phases of antigen-specific immunity in the eye. We also were the first to publish on the cornea-specific expression of the membrane-bound VEGFR-3 decoy receptor, showing how its binding to relevant ligands, VEGF-C/D, can actively maintain the cornea free of both blood and lymphatic vessels.
4. Antigen-Presenting Cells (APC)- The dominant paradigm for many years in ocular immunology was that “corneal immune privilege” was due to the cornea being devoid of any functional APC. However, our lab demonstrated in a series of papers that the cornea is indeed populated by a heterogeneous population of bone marrow-derived cells that maintain a highly immature phenotype which renders them capable of antigen pickup but poor in sensitizing T cells. Subsequent studies showed how these APC alter their phenotype in response to different inflammatory insults and what mechanisms regulate their trafficking to the lymphoid compartment for priming antigen-specific T cell responses.
5. Ocular Surface Autoimmunity and Dry Eye Disease (DED)- Our work has focused on the role of T helper-17 (Th17) cells in dry eye pathogenesis. We have shown that in chronic disease, even without ongoing desiccating stress, there is generation of memory Th17s that are critical in maintaining chronic ocular surface epithelial damage. Ongoing research is focused on determining factors that maintain Th17 memory in DED and contribution of different Th17 effectors to the memory pool.
20 Staniford Street
Boston, MA 02114