Adaptation to hypoxia is a major challenge for the survival of Mycobacterium tuberculosis (Mtb) in vivo. Interferon (IFN)-γ-producing CD8⁺ T cells contribute to control of Mtb infection, in part by promoting antimicrobial activities of macrophages. Whether Mtb counters these responses, particularly during hypoxic conditions, remains unknown. Using metabolomic, proteomic and genetic approaches, here we show that Mtb induced Rv0884c (SerC), an 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 co-culture. Mechanistically, d-serine interacted with WDR24 and inhibited mTORC1 activation in CD8⁺ T cells. This decreased T-bet expression and reduced IFN-γ production by CD8⁺ T cells. Our findings suggest an Mtb evasion mechanism where pathogen metabolic adaptation to hypoxia leads to amino acid-dependent suppression of adaptive anti-TB immunity.

适应缺氧是结核分枝杆菌（ Mtb ）在体内生存的主要挑战。产生干扰素 (IFN)-γ 的 CD8 ⁺ T 细胞有助于控制结核分枝杆菌感染，部分是通过促进巨噬细胞的抗菌活性。结核分枝杆菌是否会对抗这些反应，特别是在缺氧条件下，目前仍不清楚。利用代谢组学、蛋白质组学和遗传学方法，我们证明Mtb诱导 Rv0884c (SerC)（一种Mtb磷酸丝氨酸转氨酶）产生d-丝氨酸。这种活性增加了小鼠中Mtb 的发病机制，但并不直接影响巨噬细胞内Mtb 的存活。相反， d-丝氨酸抑制 CD8 ⁺ T 细胞产生 IFN-γ，从而间接降低了巨噬细胞在共培养时限制Mtb的能力。从机制上讲， d-丝氨酸与 WDR24 相互作用并抑制 CD8 ⁺ T 细胞中 mTORC1 的激活。这降低了 CD8 ⁺ T 细胞的 T-bet 表达并减少了 IFN-γ 的产生。我们的研究结果表明结核分枝杆菌逃避机制，其中病原体对缺氧的代谢适应导致适应性抗结核免疫的氨基酸依赖性抑制。