Biased activation of human T lymphocytes due to low extracellular pH is antagonized by B7/CD28 costimulation

As T cell response to tumor-associated antigens may be impaired by the acid ic microenvironment typical of solid tumors, we assessed the effect of extr acellular pH (pH(e)) on the activation and proliferation of human T lymphoc ytes and generation of the cytotoxic, response. T lymphocytes stimulated wi th anti-CD3 mAb or PHA at low pH(e) were unable to secrete IL-2 and IFN-gam ma and their ability to progress through the cell cycle was impaired. T lym phocytes also displayed up-regulation of IFN-gamma R2 chain and CTLA-4 expr ession, rendering them sensitive to negative regulatory signals. Agonistic mAb against CD28, but not against CD2, completely restored cytokine product ion and cell cycle progression, but down-regulated IFN-gamma R2 and CTLA-4 expression. The anti-CD28 mAb rescued the CTL response of allogeneic anti-t umor cultures generated at low pH(e). Following anti-CD28 mAb treatment, T cells synthesized cyclooxygenase-2 (Cox-2) protein, which is involved in th e early phases of T cell activation. This rescue of T cell activation was i ndependent of the inducible 6-phosphofructo-2-kinase (iPFK-2) pathway, whic h stimulates proliferation in hypoxic and acidic conditions. The restoratio n of proliferative and cytotoxic T cell responses by CD28-triggering provid es insight into the mechanisms by which B7 enhances the T cell anti-tumor r esponse in vivo.