Abstract
Mucosal associated invariant T (MAIT) cells are a class of innate-like T cells that utilize a semi-invariant αβ T cell receptor to recognize small molecule ligands produced by bacteria and fungi. Despite growing evidence that immune cells at mucosal surfaces are often phenotypically and functionally distinct from those in the peripheral circulation, knowledge about the characteristics of MAIT cells at the lung mucosal surface, the site of exposure to respiratory pathogens, is limited. HIV infection has been shown to have a profound effect on the number and function of MAIT cells in the peripheral blood, but its effect on lung mucosal MAIT cells is unknown. We examined the phenotypic, functional, and transcriptomic features of major histocompatibility complex (MHC) class I-related (MR1)-restricted MAIT cells from the peripheral blood and bronchoalveolar compartments of otherwise healthy individuals with latent Mycobacterium tuberculosis (Mtb) infection who were either HIV uninfected or HIV infected. Peripheral blood MAIT cells consistently co-expressed typical MAIT cell surface markers CD161 and CD26 in HIV-negative individuals, while paired bronchoalveolar MAIT cells displayed heterogenous expression of these markers. Bronchoalveolar MAIT cells produced lower levels of pro-inflammatory cytokine IFN-γ and expressed higher levels of co-inhibitory markers PD-1 and TIM-3 than peripheral MAIT cells. HIV infection resulted in decreased frequencies and pro-inflammatory function of peripheral blood MAIT cells, while in the bronchoalveolar compartment MAIT cell frequency was decreased but phenotype and function were not significantly altered. Single-cell transcriptomic analysis demonstrated greater heterogeneity among bronchoalveolar compared to peripheral blood MAIT cells and suggested a distinct subset in the bronchoalveolar compartment. The transcriptional features of this bronchoalveolar subset were associated with MAIT cell tissue repair functions. In summary, we found previously undescribed phenotypic and transcriptional heterogeneity of bronchoalveolar MAIT cells in HIV-negative people. In HIV infection, we found numeric depletion of MAIT cells in both anatomical compartments but preservation of the novel phenotypic and transcriptional features of bronchoalveolar MAIT cells.
Highlights
Mucosal associated invariant T (MAIT) cells are a relatively recently described group of innate-like T cells that recognize antigen presented by the highly conserved MHC class I-related (MR1) protein using the semi-invariant TCRa, TRAV1-2 [1,2,3]
Assessment of all the HIV-negative participants from the research bronchoscopy cohort found that the vast majority of peripheral blood MAIT cells had the CD161+CD26+ phenotype [median of 94.2% and interquartile range (IQR) 87.9 – 97.9%] and that this phenotype was significantly less frequent (64.95%, 39.0 – 77.88%) among MR1 tetramer-positive cells derived from the bronchoalveolar fluid (P = 0.0002) (Figure 1D)
Previous work detailing HIV-induced alterations of MAIT cells largely focused on peripheral blood responses despite there being evidence that MAIT cells may be important in the response to infection at mucosal surfaces
Summary
Mucosal associated invariant T (MAIT) cells are a relatively recently described group of innate-like T cells that recognize antigen presented by the highly conserved MHC class I-related (MR1) protein using the semi-invariant TCRa, TRAV1-2 [1,2,3]. MAIT cells classically recognize and respond to a variety of bacteria, through MR1-restricted recognition of bacterially derived riboflavin metabolites [4,5,6]. MAIT cells recognize and respond to Mycobacterium tuberculosis (Mtb) it is unclear whether this interaction is mediated via the recognition of intermediates generated by the riboflavin biosynthesis pathway [7]. MAIT cells have been found to be enriched and display pro-inflammatory function in the lungs of people with active tuberculosis (TB) [8]. MAIT cells in the lungs have been shown to be important for the production of pro-inflammatory cytokines and the recruitment of IFN-g producing T cells during the early stages of bacterial infection, while mice lacking MR1 (MR1−/−) displayed impairments in pathogen control [9]. The impact of HIV on MAIT cells at the lung’s mucosal surface is incompletely understood [19]
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