Retinal Pericytes Inhibit Activated T Cell Proliferation

Pericytes are critical for maintaining vessel stability and controlling endothelial cell proliferation.1,2 The retina has the most abundant pericyte density in the entire body.3 The loss of retinal pericytes (RPCs) is considered a hallmark of early-stage diabetic retinopathy (DR) in patients and animal studies.4 Although mice lacking pericytes die as a result of microvascular leakage and hemorrhage,5,6 mice with reduced numbers of pericytes developed microvascular lesions consistent with DR.7 Despite all these intriguing discoveries, the underlying mechanism by which RPCs contribute to retinal health and integrity remains poorly understood. Inflammation increases vascular permeability and induces edema, tissue destruction, and neovascularization, features shared by DR.8,9 Inflammation has been implicated in the pathogenesis of DR.10 In retina/vitreous of patients/animals with retinopathy, levels of inflammatory cytokines (e.g., IFN-γ and TNF-α) are increased,11,12 levels of adhesion molecules (e.g., ICAM-1) that facilitate attachment and infiltration of leukocytes are increased,13 and activated monocytes and granulocytes are identified.14 All of this mounting evidence suggests that inflammation and the immune system are integrally involved in the development of DR. In this report, using isolated human and mouse RPCs, we demonstrated, for the first time, that RPCs are immunosuppressive. These cells profoundly inhibited T cell proliferation and reduced inflammatory cytokine production. Both the cell surface proteins and released soluble factors were integrally involved in the process. Incubation with high glucose or methylglyoxal (MGO) significantly impaired the T cell inhibitory activity of RPCs, suggesting that loss of the immunosuppressive activity of RPCs under chronic hyperglycemic conditions could contribute to retinal inflammation and the development of DR.