Membrane-associated TGF-beta1 inhibits human memory T cell signaling in malignant and nonmalignant inflammatory microenvironments.
TGF-beta1 is present on cells derived from the microenvironment of human lung tumors and nonmalignant inflammatory tissues. We establish that this cell-associated cytokine mediates hyporesponsiveness of the memory T cells in these microenvironments in situ by blocking TCR signaling. T cells derived from these tissues failed to translocate NF-kappaB to the nucleus in response to CD3 + CD28 cross-linking. This nonresponsiveness was reversed by an anti-TGF-beta1-neutralizing Ab. Refractoriness of the memory T cells to TCR activation was also reversed by the removal of TGF-beta1 by briefly pulsing the cells in a low pH buffer. Addition of exogenous TGF-beta1 to eluted T cells re-established their nonresponsive state. Neither TGF-beta1, anti-TGF-beta1 Ab, nor low pH affected TCR signaling potential of peripheral blood T cells. We conclude that TGF-beta1 mediates a physiologically relevant regulatory mechanism, selective for memory T cells present in the tumor microenvironment and nonmalignant chronic inflammatory tissues.
Broderick
Lori
L
Department of Microbiology and Immunology, State University of New York, Buffalo, NY 14214, USA.
Bankert
Richard B
RB
D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007156:Immunologic Memory / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D015458:Leukemia, T-Cell / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D000906:Antibodies; D011948:Receptors, Antigen, T-Cell; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1