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Jay Jyh-Kuen Siak, Shu-Wen Tan, Xinru Lim, Kaing Woon, Samanthila Waduthantri, Soon-Phaik Chee, Anis Larbi, Nobuyo Yawata; Exhausted Senescent T-cells and Cytomegalovirus Anterior Uveitis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4933. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Cytomegalovirus (CMV) infection is associated with recurrent anterior uveitis (AU) among immunocompetent individuals and the underlying pathogenesis remains unclear. To test our hypothesis that recurrent CMV-AU might be related to an impaired systemic adaptive immunity, we compared the phenotypic characteristics of CMVpp65-specific and total CD8+ T-cells of immunocompetent Chinese with CMV- AU against that of age-matched CMV seropositive controls without uveitis.
Peripheral blood mononuclear cells (PBMC) were isolated from 36 immunocompetent Singaporean Chinese with aqueous humor PCR proven active CMV-AU at baseline and two months after treatment, and 44 immunocompetent healthy volunteers with positive CMV IgG serology. HLA class I typing was performed by Next Generation Sequencing. PBMC from HLA-A*1101+ or HLA-A*2402+donors (16 CMV-AU and 14 controls) were stained with HLA-A*1101 or A*2402 CMVpp65 peptide-loaded Dextramers (Immudex) and CD3, CD4, CD8, CCR7, CD27, CD45RA, CD95, CD57, KLRG-1, PD-1, CD56 and CD161 antibodies, followed by flow cytometry analysis on a LSRFortessa™ cell analyzer (BD Biosciences). Statistical analysis was performed using FlowJo and TSNE analysis using R-statistics software.
CMVpp65-specific CD8+T-cells of active CMV-AU subjects demonstrated a more differentiated and immuno-senescent phenotype compared to that of controls, with an increased proportion of effector memory (EM) (CCR7-CD27-CD45RA-CD95+, 42.6% vs 13.3%) and terminally differentiated effector memory (TEMRA) subsets (CCR7-CD27-CD45RA+CD95+, 6.2% vs 0.7%). When CMV-AU resolved 2 months after treatment, the EM subset decreased to 25.0% while the TEMRA subset remained at 6.3%. Median Fluorescence Intensities of CMVpp65-specific T-cells were significantly decreased for CCR7 and CD27, and increased for CD57, KLRG1 and CD161 for active CMV-AU subjects compared to controls (Mann-Whitney P-values: 0.04, <0.001, <0.001, <0.001, 0.001 respectively). Notably, a greater proportion of total CD8+T-cells demonstrated a TEMRA phenotype during active CMV-AU compared to controls (7.12% vs 3.89%, P=0.01). The TEMRA subset remained at 5.54% when CMV-AU resolved (Wilcoxon P-value=0.82).
Our data suggests that immuno-senescence of systemic total and CMV-specific CD8+T-cells may contribute towards the pathogenesis of recurrent CMV uveitis among immunocompetent individuals.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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