Mycobacterium tuberculosis produces D-serine under hypoxia to limit CD8+ T cell-dependent immunity in mice

ABSTRACT: Interferon (IFN)-γ-producing CD8+ T cells are involved in control of Mycobacterium tuberculosis (Mtb) infection, in part by promoting antimicrobial activities of macrophages. Whether Mtb counters these responses, particularly during the hypoxic conditions that arise within granulomas during infection, remains unknown. Using metabolomic, proteomic and genetic approaches, here we show that Mtb induces Rv0884c (SerC), a Mtb phosphoserine aminotransferase, to produce D-serine. This activity increased Mtb pathogenesis in mice but did not directly affect intramacrophage Mtb survival. Instead, D-serine inhibited IFN-γ production by CD8+ T cells, which indirectly reduced the ability of macrophages to restrict Mtb upon coculture. Mechanistically, D-serine interacted with WDR24, a subunit of GATOR2, and inhibited mTORC1 activation in T cells. This decreased T-bet transcription factor expression by CD8+ T cells and reduced IFN-γ production. Our findings suggest a mechanism of mycobacterial metabolic adaptation to hypoxia which leads to amino acid-dependent suppression of adaptive anti-TB immunity.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mycobacterium Tuberculosis Ofxr-32

SUBMITTER: Hongyu Cheng  

LAB HEAD: Baoxue Ge

PROVIDER: PXD050258 | Pride | 2024-08-10

REPOSITORIES: Pride