Mycobacterium tuberculosis-derived linoleic acid increases regulatory T cell function to promote bacterial survival within macrophages.

Regulatory T (Treg) cells expand during Mycobacterium tuberculosis (Mtb) infection and suppress T cell-mediated control. Whether Mtb actively contributes to this process is unclear. Here, using a genome-wide mutant library, we show that the expression of Mtb Rv1272c, an ATP-binding cassette transporter, increased under hypoxic conditions and promotes Mtb survival in vivo by increasing lecithin import, followed by the production and release of linoleic acid. Linoleic acid released by infected macrophages promoted surface trafficking of the immune checkpoint molecule cytotoxic T lymphocyte antigen 4 (CTLA-4) in Treg cells via the Ca²⁺ transporter ATP2a3. This in turn inhibited macrophage reactive oxygen species production and promoted Mtb survival inside macrophages. Rv1272c-induced linoleic acid further promoted Mtb immune evasion by increasing CTLA-4 surface trafficking on Treg cells in vivo. Mechanistically, linoleic acid interacts with ATP2a3 in Treg cells and promotes mitochondria-associated endoplasmic reticulum (ER) membrane formation. This facilitates ER-to-mitochondria Ca2+ transfer and depletion of Ca2+ in the ER, and triggers store-operated calcium entry, thus elevating cytosolic Ca2+ levels to increase Ca2+-dependent CTLA-4 surface trafficking in Treg cells. These findings reveal that Mtb can use a metabolite to manipulate host responses and promote its intracellular survival.