CD40-expressing carcinoma cells induce down-regulation of CD40 ligand (CD154) and impair T-cell functions.
The interaction of CD40 expressed by immunocompetent cells with its ligand CD154 on the surface of T-helper cells plays a crucial role in the immune response. Recently, the presence of CD40 was also demonstrated on a variety of carcinomas. Whereas the critical relevance of CD40 in cytotoxic T-cell priming via dendritic cells is already established, the biological role of CD40/CD154 interactions in nonhematopoetic cells is still unclear. In the present study we demonstrate that CD154 expression density is down-regulated on activated T cells on interaction with CD40+ tumor cells. Naive T cells cocultured with CD40+carcinoma showed impaired functionality as indicated by a reduced frequency of IFN-gamma secreting cells, reduced interleukin 2 secretion, impaired proliferation, and a lack of CD154 re-expression on restimulation. In distinction, T-cell effector lysing capacity was not impaired by CD40-expressing tumor cell targets. The present results suggest that in marked contrast to antigen-presenting cells, CD40 expression on carcinoma cells suppresses T-cell activation. Our findings support the statement that CD40 functions are context dependent and imply a new function for CD40 expressed on nonantigen-presenting cells.
Batrla
Richard
R
Institute of Immunology, University of Heidelberg, 69120 Heidelberg.
Linnebacher
Michael
M
Rudy
Wolfgang
W
Stumm
Susanne
S
Wallwiener
Diethelm
D
Gückel
Brigitte
B
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology*; D023201:CD40 Ligand / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D002277:Carcinoma / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007376:Interleukin-2; D023201:CD40 Ligand; D007371:Interferon-gamma