MAIT cell responses to intracellular and extracellular pathogens are mediated by distinct antigen presenting cells.

Mucosal-associated invariant T (MAIT) cells recognize microbial derivatives of riboflavin synthesis presented by the MHC class I-related (MR1) molecule. Although these metabolites are highly conserved among bacteria, the cells that present them remain unknown. Here, we show type-17 MAIT cells respond to diverse isolates of the extracellular pathogen Acinetobacter baumannii and promote bacterial clearance. Both hematopoietic and non-hematopoietic cells mediate MR1 presentation within the lungs and mediastinal lymph nodes (meLNs). Conversely, the type-1 MAIT cell response to the intracellular pathogen Francisella tularensis requires MR1 presentation by type-2 conventional dendritic cells (cDC2s) within meLNs and ablation of these cells or their expression of MR1 renders animals more susceptible to the infection. Although MR1 is broadly expressed at homeostasis, A. baumannii enhances MR1 on macrophages and fibroblasts, while F. tularensis increases expression on cDC2s. These results demonstrate that microbial tropism dictates which APCs mediate MR1 presentation of metabolites, revealing alternative therapeutic approaches.