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An acidic microenvironment impairs the generation of non‐major histocompatibility complex‐restricted killer cells
Author(s) -
Müller B.,
Fischer B.,
Kreutz W.
Publication year - 2000
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1046/j.1365-2567.2000.00975.x
Subject(s) - cytotoxic t cell , lymphokine activated killer cell , lymphokine , cytotoxicity , interleukin 12 , biology , major histocompatibility complex , chemistry , natural killer cell , microbiology and biotechnology , immune system , immunology , biochemistry , in vitro
Summary The microenvironment within solid tumours has often been shown to exhibit an acidic local pH. In recent studies we could demonstrate that an acidic extracellular pH (pH e ) inhibits the non‐major histocompatibility complex (MHC) ‐restricted cytotoxicity of immunocompetent effector cells. However, within tumours the activation of cytotoxic cells may already be impaired by low pH e . Therefore, we investigated the influence of acidic conditions on the generation of active killer cells. The cytotoxic activity of natural killer (NK) as well as lymphokine‐activated killer (LAK) cells against K562, Daudi and Raji cells was analysed after an activation period of 3 days at pH e 7·2–6·5. A minor reduction of pH e from 7·2 to 7·0 during the culture period resulted in a strong inhibition of the natural cytotoxicity of NK cells. Furthermore, acidic pH e below 7·2 prevented the generation of activated LAK cells by interleukin‐2 (IL‐2). The cytotoxic capacity could not be reconstituted if cells cultured at a pH e of 6·5 were returned to physiological pH for another 24 hr. Analysis of the cellular subtypes within the various cultures did not reveal differences regarding the frequencies of NK cells, CD8 + T cells, or CD4 + T cells. However, an acidic pH e clearly inhibited the activation‐induced increase of relevant adhesion molecules. The production of cytokines which are involved in the regulation of the cytotoxic process (tumour necrosis factor‐α, interferon‐γ, IL‐10, IL‐12 and transforming growth factor‐β 1 ) was also affected by pH e , as their release was strongly inhibited at pH e 7·0. Furthermore, we observed a considerable decrease in the metabolic activity of effector cells at acidic pH e . In summary, our findings suggest that an acidic microenvironment impairs the induction of an anti‐tumoral immune response within solid tumours.