MR1-Restricted MAIT Cells From The Human Lung Mucosal Surface Have Distinct Phenotypic, Functional, and Transcriptomic Features That Are Preserved in HIV Infection

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.

Human lung-resident mucosal-associated invariant T cells are abundant, express antimicrobial proteins, and are cytokine responsive

“…In addition to RORC , we found robust expression of IL17A (Fig. 2c ), concordant with our observations in both peripheral blood 34 and the lung 15 . The highest significantly upregulated gene in lung MAIT cells was SLC4A10.…”

“…We found that MAIT cells with mycobacterial reactivity are present in the airways of healthy individuals, and further enriched in bronchoalveolar fluid isolated from patients with active pulmonary tuberculosis 14 . Furthermore, bronchoalveolar MAIT cells from healthy individuals with latent tuberculosis produce less pro-inflammatory cytokines, display higher levels of inhibitory markers, and can express distinct tissue repair genes compared to peripheral MAIT cells 15 . Finally, murine models of bacterial pneumonia have uncovered a key role for MAIT cells in the lungs that proliferate in situ as opposed to being recruited from lymph nodes 16 .…”

IL-15 superagonist N-803 enhances IFNγ production and alters the trafficking of MAIT cells in SIV+ macaques

“…MAIT cells located in lung tissue and lung-associated lymph nodes may not behave the same as those derived from the PBMC (42, 43). We isolated lymphocytes from blood (PBMC), lung tissue, and tracheobronchial lymph nodes collected at necropsy from 4 SIV-infected rhesus macaques (Ellis-Connell et al, manuscript in progress; Fig.…”

Discrepancy betweenMtb-specific IFN-γ and IgG responses in HIV-positive people with low CD4 counts

“…Data and plasma from participants who were screened for the Phefumula cohort, a research bronchoscopy study described previously in Muema et al , 2020 (15) and Khuzwayo et al , 2021 (16), were used for this analysis. HIV-positive and HIV-negative adults, between 18-50 years, who were otherwise healthy (no chronic medical conditions, no current or past tobacco use, no current TB symptoms) were recruited from KwaDabeka Community Health Clinic in peri-urban KwaZulu-Natal, South Africa.…”