Mucosa-associated invariant T-cells (MAIT) are a recently characterized, novel subset of innate-like T-cells that are particularly abundant in the liver and mucosal tissues. MAIT cells express a semi-invariant T cell receptor comprised of V?7.2, limited J? segments (J?2, J?13, or J?20) an limited V? repertoires. Unlike conventional T-cells, MAIT cells recognize microbial metabolites presented by the MHC-1b-related protein MR1, including vitamin B2 (riboflavin) metabolites unique to certain bacteria and fungi. Because of their enrichment in tissues such as the gut, liver and lung, MAIT cells may be particularly important in two aspects of host defense of particular relevance to HIV infection: promoting epithelial integrity and limiting microbial translocation; an responding to opportunistic pathogens such as Mycobacteria, Candida, Salmonella and others. MAIT cell levels in peripheral blood are significantly reduced in chronic HIV infection, as recentl reported by our group and others. We hypothesize that MAIT loss or impairment contributes to persistent immune activation, and compromises host responses to bacterial and fungal pathogens. The overall goals of the project are: (a) to determine the impact of acute and chronic HIV infection on mucosal MAIT cells, and (b) to determine the ability of ART to restore MAIT levels and functionality.
IN AIM 1, we will elucidate the basis of MAIT cell loss and dysfunction i chronic HIV infection. We will assess MAIT cell levels and functionality in blood of HIV-infected subjects and controls; address mechanisms by which MAIT cells are lost during chronic HIV infection; and determine the extent to which their antimicrobial functions are restored by antiretroviral therapy (ART).
IN AIM 2, we will determine the impact of chronic HIV infection on MAIT cells in terminal ileum and rectal mucosa. We will determine the abundance and functionality of MAIT cells in these tissues, and will address the relationship between MAIT function and immune activation signatures in chronic HIV infection in subjects on and off ART.
IN AIM 3, we will determine the dynamics of peripheral and intestinal MAIT cells in acute HIV infection and relate this information to differential disease outcomes and responses to early ART. This project is a collaborative effort involving three Co-PIs and their laboratories: Dr. Barbara Shacklett (contact PI, UC Davis), Dr. Johan Sandberg (Karolinska Institute), and Dr. Michael Eller (HJF/MHRP). The project addresses mechanisms of impaired gastrointestinal mucosal immunity in people with HIV, and is submitted in response to RFA-DK-14-019.

Public Health Relevance

Mucosa-associated invariant T-cells (MAIT) are a recently described type of white blood cell that plays a major role in host defense against disease-causing bacteria and fungi. Because MAIT cells were recently discovered, very little is known about how they are affected by HIV infection. This project has two major goals: to better understand how and why MAIT cells are killed or damaged during HIV infection; and to test whether taking anti-HIV drugs can restore MAIT cells, or improve their function, in HIV-infected people

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK108350-04
Application #
9552142
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Perrin, Peter J
Project Start
2015-09-22
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Davis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Dias, Joana; Boulouis, Caroline; Gorin, Jean-Baptiste et al. (2018) The CD4-CD8- MAIT cell subpopulation is a functionally distinct subset developmentally related to the main CD8+ MAIT cell pool. Proc Natl Acad Sci U S A 115:E11513-E11522
Lal, Kerri G; Leeansyah, Edwin; Sandberg, Johan K et al. (2018) OMIP-046: Characterization of invariant T cell subset activation in humans. Cytometry A 93:499-503
Dias, Joana; Boulouis, Caroline; Sobkowiak, Micha? J et al. (2018) Factors Influencing Functional Heterogeneity in Human Mucosa-Associated Invariant T Cells. Front Immunol 9:1602
Sortino, Ornella; Richards, Elizabeth; Dias, Joana et al. (2018) IL-7 treatment supports CD8+ MAIT cell restoration in HIV-1 infected patients on ART. AIDS :
Dias, Joana; Leeansyah, Edwin; Sandberg, Johan K (2017) Multiple layers of heterogeneity and subset diversity in human MAIT cell responses to distinct microorganisms and to innate cytokines. Proc Natl Acad Sci U S A 114:E5434-E5443
Gibbs, A; Leeansyah, E; Introini, A et al. (2017) MAIT cells reside in the female genital mucosa and are biased towards IL-17 and IL-22 production in response to bacterial stimulation. Mucosal Immunol 10:35-45
Dias, Joana; Sobkowiak, Micha? J; Sandberg, Johan K et al. (2016) Human MAIT-cell responses to Escherichia coli: activation, cytokine production, proliferation, and cytotoxicity. J Leukoc Biol 100:233-40