Abstract
Purpose :
In CMV anterior uveitis (CMV-AU), recurrent intraocular inflammation is triggered by CMV reactivation in individuals in the absence of apparent systemic immunodeficiency. NK cells are innate lymphocytes regulating CMV infection, and NKG2C has been considered an NK cell receptor that is utilized to recognize CMV infection in human. CMV infection is known to induce immunosenescence and leave an imprint on the NK cell receptor repertoire. NKG2C+CD57+NK cells expand in CMV seropositive human individuals, whereas Ly49H+KLRG1+NK cells expand in rodents where NKG2C and CD57 are absent. To assess NK cell profiles in CMV-AU, we compared the peripheral NK cell profiles in CMV-AU against those in CMV seropositive healthy individuals with maturation markers used in human (CD57) and rodents (KLRG1).
Methods :
Peripheral blood mononuclear cells were isolated from 15 CMV-AU patients, 15 age-matched CMV seropositive healthy individuals, and 3 CMV seronegative individuals. We analyzed the NK cell profiles of receptors thought to be involved in CMV recognition in association with NK cell maturation markers: KLRG1, CD57, Killer cell Immunoglobulin-like receptors (KIRs), NKG2C, and NKG2A using high-dimensional flow cytometry. A CMV-pp65 random peptide library was tested for the capacity to induce proinflammatory cytokine responses in NK cells.
Results :
We identified four distinct NK subsets determined by KLRG1 and CD57 expression regardless of CMV serostatus. Expression profiles of KIRs and NKG2A in each subset implies that the CD57+KLRG1- subset is most differentiated followed by the CD57+KLRG1+ subset. These two subsets were the most dominant in CMV-AU and CMV seropositive healthy controls. NKG2C expression frequencies were diverse (2-82%) and the distribution pattern was different between CMV-AU and CMV seropositive controls. Notably, significant increase of IFN-g production was observed in the CD57+KLRG1+NKG2C- NK cells upon CMV-pp65 stimulation. Expression cluster analysis identified NK subsets unique to CMV-AU, which could be responsive to CMV-pp65.
Conclusions :
These results infer that human NK cells utilize receptors other than NKG2C for CMV recognition and differences in anti-CMV immunity mediated by peripheral NK cells are involved in the development of CMV-AU.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.