title: Effects of extracellular pH and hypoxia on the function and development of antigen-specific cytotoxic T lymphocytes.
abstract: The major effector cells for cellular adaptive immunity are CD8(+) cytotoxic T lymphocytes (CTLs), which can recognize and kill virus-infected cells and tumor cells. Although CTLs exhibit strong cytolytic activity against target cells in vitro, a number of studies have demonstrated that their function is often impaired within tumors. Nevertheless, CTLs can regain their cytotoxic ability after escaping from the tumor environment, suggesting that the milieu created by tumors may affect the function of CTLs. As for the tumor environment, the patho-physiological situation present in vivo has been shown to differ from in vitro experimental conditions. In particular, low pH and hypoxia are the most important microenvironmental factors within growing tumors. In the present study, to determine the effect of these factors on CTL function in vivo, we examined the cytolytic activity of CTLs against their targets using murine CTL lines and the induction of these cells from memory cells under low pH or hypoxic conditions using antigen-primed spleen cells. The results indicated that both cytotoxic activity and the induction of functional CTLs were markedly inhibited under low pH. In contrast, in hypoxic conditions, although cytotoxic activity was almost unchanged, the induction of CTLs in vitro showed a slight enhancement, which was completely abrogated in low pH conditions. Therefore, antigen-specific CTL functions may be more vulnerable to low pH than to the oxygen concentration in vivo. The findings shown here provide new therapeutic approaches for controlling tumor growth by retaining CTL cytotoxicity through the maintenance of higher pH conditions.
authors.affiliation: Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, Japan. Electronic address: tanuki@nms.ac.jp.
authors.forename: Yohko
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Negishi
authors.affiliation: Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, Japan.
authors.forename: Masumi
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo 113-8602, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Ichikawa
authors.affiliation: Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D000138:Acidosis / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005110:Extracellular Space; D005260:Female; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010101:Oxygen Consumption; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000941:Antigens; D018984:Epitopes, T-Lymphocyte; D010047:Ovalbumin
keywords: Cytotoxic T lymphocytes; Extracellular pH; Hypoxia; Low pH