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 acidic microenvironment typical of solid tumors, we assessed the effect of extracellular pH (pH(e)) on the activation and proliferation of human T lymphocytes and generation of the cytotoxic response. T lymphocytes stimulated with anti-CD3 mAb or PHA at low pH(e) were unable to secrete IL-2 and IFN-gamma and their ability to progress through the cell cycle was impaired. T lymphocytes also displayed up-regulation of IFN-gammaR2 chain and CTLA-4 expression, rendering them sensitive to negative regulatory signals. Agonistic mAb against CD28, but not against CD2, completely restored cytokine production and cell cycle progression, but down-regulated IFN-gammaR2 and CTLA-4 expression. The anti-CD28mAb rescued the CTL response of allogeneic anti-tumor cultures generated at low pH(e). Following anti-CD28 mAb treatment, T cells synthesized cyclooxygenase-2 (Cox-2) protein, which is involved in the early phases of T cell activation. This rescue of T cell activation was independent of the inducible 6-phosphofructo-2-kinase (iPFK-2) pathway, which stimulates proliferation in hypoxic and acidic conditions. The restoration of proliferative and cytotoxic T cell responses by CD28-triggering provides insight into the mechanisms by which B7 enhances the T cell anti-tumor response in vivo.
Bosticardo
M
M
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
Ariotti
S
S
Losana
G
G
Bernabei
P
P
Forni
G
G
Novelli
F
F
D000069594:Abatacept; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism*; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000096:biosynthesis; D005110:Extracellular Space / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018796:Immunoconjugates; D007527:Isoenzymes / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008565:Membrane Proteins; D009374:Neoplasms, Experimental / Q000276:immunology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D017471:Receptors, Interferon / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D011990:Receptors, Transferrin; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured; D000096743:Interferon gamma Receptor
D000069594:Abatacept; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000944:Antigens, Differentiation, B-Lymphocyte; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D051546:Cyclooxygenase 2; D016207:Cytokines; D018796:Immunoconjugates; D007527:Isoenzymes; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D017471:Receptors, Interferon; D015375:Receptors, Interleukin-2; D011990:Receptors, Transferrin; D000096743:Interferon gamma Receptor; C068126:CD71 antigen; C556706:CTLA4 protein, human; C496540:PTGS2 protein, human