Elucidating NK-DC crosstalk in autoimmune uveitis disease

Abstract

Purpose : Uveitis is a significant cause of severe visual handicap in the United States as well as in rest of the world, however, our understanding of driving mechanisms and treatment options are limited. Evidence links induction of experimental autoimmune uveitis to T cell mediated pathogenesis which is broadly regulated by the crosstalk between natural killer (NK) cell and dendritic cell (DC). Here we present the analysis of major immune cell population in the peripheral blood lymphocytes (PBMCs) of uveitis patients with a focus on potential NK-DC crosstalk.

Methods : Flow cytometry-based analysis of PBMCs from 150 non-infectious uveitis patients and 65 healthy individuals is performed using samples from a prospective clinical study (NCT02656381). Multicolor flow panels were designed to interrogate subsets of T cells, NK cells and monocyte/DCs in freshly isolated peripheral blood of uveitis patients as well as healthy donors.

Results : Significant upregulation of CD56^dimCD16^bright NK cells (p = 0.0023) and concomitant downregulation of DC subsets such as IL3R⁺ plasmacytoid DCs (pDCs, p = 0.003) as well as BDCA-3⁺ myeloid dendritic cells (cDCs, p < 0.0001) in uveitis PBMCs were observed. T cell subset analysis revealed a significant expansion of CD8⁺ T effector memory CD45RA⁺ cells (p = 0.0183) in uveitis patients. Moreover, expression of costimulatory receptor CD28 in this subset of T cells had been significantly downregulated (p < 0.0001), suggesting terminal differentiation of CD8⁺ T cells in uveitis patients.

Conclusions : NK-DC interaction in lymph node draining site of immunization has long been studied, however, NK cells as an active modulator of autoimmune responses in patients, particularly in uveitis, has not been extensively explored. A previous study involving blockade of IL2Rα (daclizumab) in uveitis patients showed expansion of CD56^bright NK cells whose immunomodulatory effects appeared to inhibit activated T cell survival. We have found an elevation of CD56^dimCD16^bright NK cells in patients’ peripheral blood, indicating basal expansion of activated NK cells in uveitis patients. Concomitant decrease of DCs and increase of terminally differentiated CD8+ T cells suggest both cytotoxic and regulatory role of NK cells in uveitis patients which need to be further examined.

This is a 2020 ARVO Annual Meeting abstract.