Acidity suppresses T cell function and increases memory T cell development

Acidity is a common microenvironmental factor in solid tumors. We and others have observed that mild acidosis (pH ~6.6) can inhibit the interferon‐γ (IFN‐γ) production by CD8+ T cells and suppress the T‐cell mediated anti‐tumor cell cytolysis. However, the mechanism by which acidosis inhibits effector fuction of T‐cells is not fully understood. Here we show the inhibition of IFN‐γ production by acidity is titratable and is not transduced through the inhibition of major proton‐sensing transporters, such as TDAG8, OGR1, ASIC‐3, or ADIC‐4, all of which we show are expressed in T cells. Neither pharmacologically blockade nor genetic knockout of these transporters could precent the inhibition of IFN‐γ or IL‐2 production by acidosis. Acidosis also inhibited the secretion of other important cytokines by T cells. However, secretion of MDC, MIG, and IP‐10, was increased under acidic pH, indicating that acidosis is not working through a general inhibition of secretion. Acid treated T cells showed the same kinetics of cytokine production compared with non‐treated cells when re‐stimulated under normal physiological pH. These together suggest the inhibition is not due to general failure of cell activity. Furthermore, we found that T cell can be successfully activated under low pH, evidenced by cell surface marker profile change, but more cells were directed to a memory T cell phenotype, suggesting that the acidity directs T cells to differentiate to memory status. Mechanically, extracellular acidification potentaly inhibited the monocarboxylated transporter, MCT1, blocking lactate and H+ efflux leading to an inhibition of glycolysis, which is required for effector T cell function. Support or Funding Information This work is supported by Team Science project of Moffitt Cancer Center This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .