Person:

Chauhan, Sunil

The normal cornea is devoid of lymphatic and blood vessels, thus suppressing both the afferent (lymphatic) and efferent (vascular) arms of the immune response–contributing to its ‘immune privilege’. Inflammation, however, negates this unique ‘immune’ and ‘angiogenic’ privilege of the cornea. Abnormal blood vessel growth from pre-existing limbal vessels into the cornea has been studied for many years, but it is only recently that the significance of new lymphatic vessels (lymphangiogenesis) in ocular inflammatory diseases has been demonstrated. Whereas blood vessels in inflamed ocular surface provide a route of entry for immune effector cells to the cornea, lymphatics facilitate the exit of antigen-presenting cells and antigenic material from the cornea to regional lymph nodes, thus promoting induction of adaptive immune response. This review summarizes the current evidence for lymphangiogenesis in the cornea, and describes its molecular mediators; and discusses the interface between corneal lymphangiogenesis and adaptive immunity. Furthermore, the pathophysiologic implications of corneal lymphangiogenesis in the setting of allo- and autoimmune-mediated corneal inflammation are discussed.

Regulatory T cells (Tregs) are instrumental in the induction and maintenance of tolerance, including in transplantation. Tregs induce allotolerance by interacting with antigen-presenting cells (APC) and T cells, interactions that require their proper homing to the lymphoid tissues. Using a well characterized model of corneal allotransplantation, we demonstrate here that Tregs in the draining LN of allograft acceptors, but not rejectors, colocalize with APC in the paracortical areas and express high levels of C-C motif chemokine receptor 7 (CCR7). In addition, we show that Treg expression of CCR7 is important not only for Treg homing to the draining LN, but also for optimal Treg suppressive function. Finally, we show that Tregs augmented for CCR7 expression by their ex vivo stimulation with the CCR7-ligand CCL21 show enhanced homing to the draining LN of allograft recipients and promote transplant survival. Together, these findings suggest that CCR7 expression is critical for Treg function and migration, and that conditioning of Treg for maximal CCR7 expression may be a viable strategy for promoting allograft survival.