P11. Exploring the role of MAIT cells in HIV-1 immunopathogenesis.
Edwin Leeansyah1, Jenny Svärd2 , Anupama Ganesh3 , Joana Dias1 , Marcus Buggert4 , Jessica Nyström4 , Markus Moll1 , Anders Sönnerborg2,4 , Piotr Nowak2,4 , Barbara L Shacklett3 , Johan K Sandberg1
Affiliates: 1Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. 2Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. 3Department of Medical Microbiology and Immunology, University of California, Davis, Davis, CA, USA. 4Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
Mucosal-associated invariant T (MAIT) cells represent a large, innate-like antimicrobial T cell subset in humans that recognise riboflavin metabolites from a range of microbes presented by MR1 molecules. MAIT cells are impaired in several chronic diseases including HIV-1 infection, where we previously found that they show signs of exhaustion and persistent numerical decline in circulation of chronic HIV-1-infected patients. MAIT cells in rectal mucosa were relatively preserved, although some of the changes seen in blood were recapitulated in the mucosa. In the present study, we investigated the MAIT cell responses to bacteria in humans infected with HIV-1, and possible means to restore functionality to these cells. Residual MAIT cells failed to mobilise components of the cytolytic effector machinery and were unable to produce antibacterial cytokines in response to bacteria. The functionally impaired MAIT cell population exhibited loss of critical transcription factors that correlated with the deficiency in cytotoxic capacity and cytokine production. Effective antiretroviral therapy did not fully restore these aberrations. Interestingly, IL-7, a cytokine that plays a key role in T cell survival and homeostasis, had strong effects on MAIT cells, including the arming of cytolytic function, enhanced sensitivity for low levels of bacteria, and augmented killing of bacteria-pulsed cells. In HIV-infected patients, plasma IL-7 levels were positively associated with the size of the MAIT cell population, and IL-7 could rescue MAIT cell aberrant transcriptional profile and defective function in vitro. These findings indicate that MAIT cell impairment in HIV-1 infection is broad-based, including loss of critical transcription factors, antibacterial cytokines, as well as cytolytic function. The decline in MAIT cell levels and function may seriously impair the ability to mount immune responses against microbial pathogens. Finally, our data support the notion that IL-7 is a strong candidate for immunotherapy in diseases associated with MAIT cell loss.