Macrophage MR1 antigen presentation promotes MAIT cell immunity and lung microbiota modulation.
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| Title: | Macrophage MR1 antigen presentation promotes MAIT cell immunity and lung microbiota modulation. |
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| Authors: | Deng, Jieru (AUTHOR), Yan, Yuting (AUTHOR), Zhang, Xiaoyue (AUTHOR), Walsh, Calum J. (AUTHOR), Montassier, Emmanuel (AUTHOR), Sinha, Debajyoti (AUTHOR), Wang, Huimeng (AUTHOR), Mousavizadeh, Atieh (AUTHOR), Ashayeripanah, Mitra (AUTHOR), Mak, Jeffrey Y. W. (AUTHOR), Koay, Hui-Fern (AUTHOR), Poch, Tobias (AUTHOR), Alexandre, Yannick O. (AUTHOR), Mueller, Scott N. (AUTHOR), Vasanthakumar, Ajithkumar (AUTHOR), Stinear, Tim P. (AUTHOR), Jameson, Vanta J. (AUTHOR), Perez-Gonzalez, Alexis (AUTHOR), Kingham, Jenny (AUTHOR), Phan, Tri Giang (AUTHOR) |
| Source: | Science. 1/15/2026, Vol. 391 Issue 6782, p1-15. 15p. |
| Subjects: | Macrophages, Antigen presentation, Microbiota, Antigen presenting cells, Infection, T cells, Bacterial antigens, Immune response |
| Abstract: | Mucosal-associated invariant T cells (MAIT cells) mediate tissue homeostasis and antimicrobial immunity. However, the cells that express major histocompatibility complex (MHC) class I–related protein 1 (MR1) and present microbial vitamin B–derived antigens (VitBAg) to MAIT cells remain unknown. We found that MR1 expression varied across tissues and cell types. Macrophages from the lung and peritoneal cavity expressed the highest levels of MR1 and were the most efficient at capturing and presenting VitBAg to MAIT cells. Expression of MR1 in macrophages was regulated transcriptionally and induced by the tissue environment and microbiota. Depletion of MR1 in macrophages, dendritic cells, and monocytes changed the composition of the microbiota and impaired MAIT cell responses against bacterial infection. We concluded that macrophages are key for MR1 antigen presentation and MAIT cell immunity. Editor's summary: Mucosal associated invariant T cells, or MAIT cells, contribute to immune protection against microbial pathogens. These cells are stimulated by other cells that present microbial metabolites using a protein called MHC class I-related protein 1 (MR1), but the identity of these antigen-presenting cells has not been established. Deng et al. created a mouse model to facilitate the identification of MR1-expressing cells. Macrophages from the lung and peritoneal cavity expressed the highest levels of MR1 and were efficient at capturing and presenting antigens to MAIT cells. Depletion of MR1 in macrophages impaired the ability of mice to clear systemic and lung bacterial infections and altered the lung microbiota. —Sarah H. Ross INTRODUCTION: The immune system consists of cells that detect microorganisms with varying degrees of selectivity. Many cell types react against components found in most viruses or bacteria, whereas only a few among a huge number of T and B lymphocytes react against a specific fragment of an individual pathogen. Mucosal associated invariant T cells (MAIT cells) sit between these extremes. They are abundant but highly specific for vitamin B–derived antigens (VitBAg), small molecules produced only by bacteria and fungi. VitBAg detection enables MAIT cells to "sense" and interact with the healthy microbiome and to respond against pathogens. However, MAIT cells can only detect VitBAg that have been captured and displayed, bound to the receptor MR1, on the surface of antigen-presenting cells (APCs). The identity of this APC has remained elusive, hampering development of therapies that might exploit the immune functions of MAIT cells. RATIONALE: The MR1-MAIT cell axis is highly conserved in mammals. It was reasonable to assume that a specific cell type would also have a conserved, dominant role in MR1-VitBAg presentation. We hypothesized that such an APC would synthesize more MR1 protein, obtain microbial VitBAg more effectively, and display higher levels of MR1-VitBAg complexes than those of other cells. We generated a genetically modified mouse strain in which cells accumulate a fluorescent protein at levels proportional to the amount of MR1 they produced. This facilitated identification of candidate APCs specialized at VitBAg presentation in tissues that we could investigate to determine their ability to capture VitBAg, produce MR1-VitBAg complexes, and engage in interactions with MAIT cells. In addition, selective deletion of MR1 in candidate APCs would allow their relevance in regulating MAIT cell function to be understood. RESULTS: In mice, MR1 expression was greatest in tissue-resident macrophages, particularly in lung and body cavity macrophages. Similarly in humans, macrophages had the greatest levels in lung and spleen cells examined. MR1 protein abundance was increased in macrophages through tissue-specific environmental cues and microbiota-derived signals. These pathways depended on MyD88 expression in macrophages, indicating that Toll-like receptor signaling promoted MR1 expression. Mice in which MR1 expression was selectively eliminated in macrophages and other myeloid cells had normal numbers of MAIT cells. However, these mice showed an altered lung microbiota, mounted defective MAIT cell responses against infecting bacteria, and showed impaired pathogen clearance. Side-by-side comparisons of multiple cell types—including dendritic cells, B cells, and T cells—confirmed the superior ability of macrophages to carry out MR1-VitBAg presentation and MAIT cell activation. CONCLUSION: Macrophages acted as MR1 APCs that orchestrated MAIT cell responses to microbial antigens. Their high MR1 expression, efficient ligand uptake, and tissue localization positions them as key regulators of MAIT cell–mediated immunity and microbiota homeostasis. Although other APCs may also present MR1-bound antigens, the extent of their involvement remains unclear. We propose that macrophages act as central players in MR1 antigen presentation and are potential targets for immunotherapeutic strategies that involve MAIT cells and MR1-restricted T cells. Macrophages are key MR1 APCs to MAIT cells.: Macrophages express high levels of MR1 and are primed to capture vitamin B–related antigens that originate from the microbiota or bacterial pathogens. These antigens are presented to MAIT cells, triggering their activation. Once activated, MAIT cells can modulate the composition of the microbiota or help to control pathogenic infections. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Mucosal-associated invariant T cells (MAIT cells) mediate tissue homeostasis and antimicrobial immunity. However, the cells that express major histocompatibility complex (MHC) class I–related protein 1 (MR1) and present microbial vitamin B–derived antigens (VitBAg) to MAIT cells remain unknown. We found that MR1 expression varied across tissues and cell types. Macrophages from the lung and peritoneal cavity expressed the highest levels of MR1 and were the most efficient at capturing and presenting VitBAg to MAIT cells. Expression of MR1 in macrophages was regulated transcriptionally and induced by the tissue environment and microbiota. Depletion of MR1 in macrophages, dendritic cells, and monocytes changed the composition of the microbiota and impaired MAIT cell responses against bacterial infection. We concluded that macrophages are key for MR1 antigen presentation and MAIT cell immunity. Editor's summary: Mucosal associated invariant T cells, or MAIT cells, contribute to immune protection against microbial pathogens. These cells are stimulated by other cells that present microbial metabolites using a protein called MHC class I-related protein 1 (MR1), but the identity of these antigen-presenting cells has not been established. Deng et al. created a mouse model to facilitate the identification of MR1-expressing cells. Macrophages from the lung and peritoneal cavity expressed the highest levels of MR1 and were efficient at capturing and presenting antigens to MAIT cells. Depletion of MR1 in macrophages impaired the ability of mice to clear systemic and lung bacterial infections and altered the lung microbiota. —Sarah H. Ross INTRODUCTION: The immune system consists of cells that detect microorganisms with varying degrees of selectivity. Many cell types react against components found in most viruses or bacteria, whereas only a few among a huge number of T and B lymphocytes react against a specific fragment of an individual pathogen. Mucosal associated invariant T cells (MAIT cells) sit between these extremes. They are abundant but highly specific for vitamin B–derived antigens (VitBAg), small molecules produced only by bacteria and fungi. VitBAg detection enables MAIT cells to "sense" and interact with the healthy microbiome and to respond against pathogens. However, MAIT cells can only detect VitBAg that have been captured and displayed, bound to the receptor MR1, on the surface of antigen-presenting cells (APCs). The identity of this APC has remained elusive, hampering development of therapies that might exploit the immune functions of MAIT cells. RATIONALE: The MR1-MAIT cell axis is highly conserved in mammals. It was reasonable to assume that a specific cell type would also have a conserved, dominant role in MR1-VitBAg presentation. We hypothesized that such an APC would synthesize more MR1 protein, obtain microbial VitBAg more effectively, and display higher levels of MR1-VitBAg complexes than those of other cells. We generated a genetically modified mouse strain in which cells accumulate a fluorescent protein at levels proportional to the amount of MR1 they produced. This facilitated identification of candidate APCs specialized at VitBAg presentation in tissues that we could investigate to determine their ability to capture VitBAg, produce MR1-VitBAg complexes, and engage in interactions with MAIT cells. In addition, selective deletion of MR1 in candidate APCs would allow their relevance in regulating MAIT cell function to be understood. RESULTS: In mice, MR1 expression was greatest in tissue-resident macrophages, particularly in lung and body cavity macrophages. Similarly in humans, macrophages had the greatest levels in lung and spleen cells examined. MR1 protein abundance was increased in macrophages through tissue-specific environmental cues and microbiota-derived signals. These pathways depended on MyD88 expression in macrophages, indicating that Toll-like receptor signaling promoted MR1 expression. Mice in which MR1 expression was selectively eliminated in macrophages and other myeloid cells had normal numbers of MAIT cells. However, these mice showed an altered lung microbiota, mounted defective MAIT cell responses against infecting bacteria, and showed impaired pathogen clearance. Side-by-side comparisons of multiple cell types—including dendritic cells, B cells, and T cells—confirmed the superior ability of macrophages to carry out MR1-VitBAg presentation and MAIT cell activation. CONCLUSION: Macrophages acted as MR1 APCs that orchestrated MAIT cell responses to microbial antigens. Their high MR1 expression, efficient ligand uptake, and tissue localization positions them as key regulators of MAIT cell–mediated immunity and microbiota homeostasis. Although other APCs may also present MR1-bound antigens, the extent of their involvement remains unclear. We propose that macrophages act as central players in MR1 antigen presentation and are potential targets for immunotherapeutic strategies that involve MAIT cells and MR1-restricted T cells. Macrophages are key MR1 APCs to MAIT cells.: Macrophages express high levels of MR1 and are primed to capture vitamin B–related antigens that originate from the microbiota or bacterial pathogens. These antigens are presented to MAIT cells, triggering their activation. Once activated, MAIT cells can modulate the composition of the microbiota or help to control pathogenic infections. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adr6322 |
