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Early and nonreversible decrease of CD161++ /MAIT cells in HIV infection.

ABSTRACT: HIV infection is associated with immune dysfunction, perturbation of immune-cell subsets and opportunistic infections. CD161++ CD8+ T cells are a tissue-infiltrating population that produce IL17A, IL22, IFN, and TNF?, cytokines important in mucosal immunity. In adults they dominantly express the semi-invariant TCR V?7.2, the canonical feature of mucosal associated invariant T (MAIT) cells and have been recently implicated in host defense against pathogens. We analyzed the frequency and function of CD161++ /MAIT cells in peripheral blood and tissue from patients with early stage or chronic-stage HIV infection. We show that the CD161++ /MAIT cell population is significantly decreased in early HIV infection and fails to recover despite otherwise successful treatment. We provide evidence that CD161++ /MAIT cells are not preferentially infected but may be depleted through diverse mechanisms including accumulation in tissues and activation-induced cell death. This loss may impact mucosal defense and could be important in susceptibility to specific opportunistic infections in HIV.

SUBMITTER: Cosgrove C

PROVIDER: S-EPMC3567342 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Early and nonreversible decrease of CD161++ /MAIT cells in HIV infection.

Cosgrove Cormac C Ussher James E JE Rauch Andri A Gärtner Kathleen K Kurioka Ayako A Hühn Michael H MH Adelmann Krista K Kang Yu-Hoi YH Fergusson Joannah R JR Simmonds Peter P Goulder Philip P Hansen Ted H TH Fox Julie J Günthard Huldrych F HF Khanna Nina N Powrie Fiona F Steel Alan A Gazzard Brian B Phillips Rodney E RE Frater John J Uhlig Holm H Klenerman Paul P

Blood 20121218 6

HIV infection is associated with immune dysfunction, perturbation of immune-cell subsets and opportunistic infections. CD161++ CD8+ T cells are a tissue-infiltrating population that produce IL17A, IL22, IFN, and TNFα, cytokines important in mucosal immunity. In adults they dominantly express the semi-invariant TCR Vα7.2, the canonical feature of mucosal associated invariant T (MAIT) cells and have been recently implicated in host defense against pathogens. We analyzed the frequency and function ...[more]

PMID: 23255555

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Project description:Both HIV and HCV infections feature increased microbial translocation (MT) and gut dysbiosis that affect immune homeostasis and disease outcome. Given their commitment to antimicrobial mucosal immunity, we investigated mucosal-associated invariant T (MAIT) cells and Vα7.2+CD161- T-cell frequency/function and their possible associations with MT and gut dysbiosis, in chronic HIV and/or HCV infections. We enrolled 56 virally infected (VI) patients (pts): 13 HIV+ on suppressive cART (HIV-RNA < 40cp/ml), 13 HCV+ naive to DAA (direct-acting antiviral) anti-HCV agents; 30 HCV+/HIV+ on suppressive cART and naive to anti-HCV. 13 age-matched healthy controls (HC) were enrolled. For Vα7.2+CD161++ and Vα7.2+CD161-CD8+ T cells we assessed: activation (CD69), exhaustion (PD1/CD39), and cytolytic activity (granzymeB/perforin). Following PMA/ionomycin and Escherichia coli stimulation we measured intracellular IL17/TNFα/IFNγ. Markers of microbial translocation (Plasma LPS, 16S rDNA, EndoCAb and I-FABP) were quantified. In 5 patients per group we assessed stool microbiota composition by 16S targeted metagenomics sequencing (alpha/beta diversity, relative abundance). Compared to controls, virally infected pts displayed significantly lower circulating Vα7.2+CD161++CD8+ MAIT cells (p = 0.001), yet expressed higher perforin (p = 0.004) and granzyme B (p = 0.002) on CD8+ MAIT cells. Upon E. coli stimulation, the residual MAIT cells are less functional particularly those from HIV+/HCV+ patients. Conversely, in virally infected pts, Vα7.2+CD161-CD8+ cells were comparable in frequency, highly activated/exhausted (CD69+: p = 0.002; PD-1+: p = 0.030) and with cytolytic potential (perforin+: p < 0.0001), yet were poorly responsive to ex vivo stimulation. A profound gut dysbiosis characterized virally infected pts, especially HCV+/HIV+ co-infected patients, delineating a Firmicutes-poor/Bacteroidetes-rich microbiota, with significant associations with MAIT cell frequency/function. Irrespective of mono/dual infection, HIV+ and HCV+ patients display depleted, yet activated/cytolytic MAIT cells with reduced ex vivo function, suggesting an impoverished pool, possibly due to continuous bacterial challenge. The MAIT cell ability to respond to bacterial stimulation correlates with the presence of Firmicutes and Bacteroidetes, possibly suggesting an association between gut dysbiosis and MAIT cell function and posing viral-mediated dysbiosis as a potential key player in the hampered anti-bacterial MAIT ability.

Dataset Information

Early and nonreversible decrease of CD161++ /MAIT cells in HIV infection.

Publications

Early and nonreversible decrease of CD161++ /MAIT cells in HIV infection.

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