Chronic Viral Infection Compromises the Quality of Circulating Mucosal-Associated Invariant T Cells and Follicular T Helper Cells via Expression of Inhibitory Receptors

Background: Chronic viral infection results in impaired immune responses rendering viral persistence. Here, we compared the quality of T-cell responses among chronic hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV)-infected individuals by examining the levels of expression of selected immune activation and exhaustion molecules on circulating MAIT cells and Tfh cells. Methods: Cytokines were measured using a commercial Bio-plex Pro Human Cytokine Grp I Panel 17-plex kit (BioRad, Hercules, CA, USA). Inflammation was assessed by measuring an array of plasma cytokines, and phenotypic alterations in CD4(+) T cells including circulating Tfh cells, CD8(+) T cells, and TCR iV alpha 7.2(+) MAIT cells in chronic HBV, HCV, and HIV-infected patients and healthy controls. The cells were characterized based on markers pertaining to immune activation (CD69, ICOS, and CD27) proliferation (Ki67), cytokine production (TNF-alpha, IFN-gamma) and exhaustion (PD-1). The cytokine levels and T cell phenotypes together with cell markers were correlated with surrogate markers of disease progression. Results: The activation marker CD69 was significantly increased in CD4(+hi) T cells, while CD8(+) MAIT cells producing IFN-gamma were significantly increased in chronic HBV, HCV and HIV infections. Six cell phenotypes, viz., TNF-alpha(+)CD4(+lo) T cells, CD69(+)CD8(+) T cells, CD69(+)CD4(+) MAIT cells, PD-1(+)CD4(+hi) T cells, PD-1(+)CD8(+) T cells, and Ki67(+)CD4(+) MAIT cells, were independently associated with decelerating the plasma viral load (PVL). TNF-alpha levels showed a positive correlation with increase in cytokine levels and decrease in PVL. Conclusion: Chronic viral infection negatively impacts the quality of peripheral MAIT cells and Tfh cells via differential expression of both activating and inhibitory receptors.
Funding Agencies|Department of Science and Technology-Science and Engineering Research Board, Government of India [CRG/2019/006096]; Swedish Research Council; Swedish, Physicians against AIDS Research Foundation; Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University Hospital Research Fund; CALF; Swedish Society of Medicine; NIH Office of Research Infrastructure Programs [P51 OD011132]; Emory CFAR [P30 AI050409]; Xiamen University Malaysia Research Fund [XMUMRF/2020C5/ITCM/0003]; Start-Up-Grant from the Department of Health Research, Government of India [12020/04/2018-HR]; [AI52731]