ON THE MECHANISMS BY WHICH TRANSFORMING GROWTH-FACTOR-BETA-2 ALTERS ANTIGEN-PRESENTING ABILITIES OF MACROPHAGES ON T-CELL ACTIVATION

Peritoneal exudate cells (PEC) incubated with antigen in the presence of transforming growth factor-(TGF)-beta 2 selectively suppress delaye d hypersensitivity and IgG2a antibody production when injected intrave nously into naive syngeneic recipients. In this study, we have examine d in vitro the effects of TGF-beta 2 on the antigen presenting abiliti es of PEC to activate DO11.10 T cells that express a transgenic T cell receptor that recognizes ovalbumin peptide fragment 323-339 in the co ntext of I-A(d). PEC were pretreated overnight with TGF-beta 2, washed extensively, then co-cultured with DO11.10 T cells in the presence of native OVA or P323-339. We found that TGF-beta 2-treated PEC induced the production of the T helper type 2 (Th2) cytokine, interleukin-4 (I L-4), but unlike untreated PEC, were unable to stimulate the Th1 cytok ines, IL-2 and interferon-gamma (IFN-gamma). Furthermore, TGF-beta 2 w as produced in an autocrine fashion by TGF-beta 2-treated PEC and was responsible for this shift to a Th2 response. This conclusion was supp orted by the following results. First, TGF-beta 2-treated PEC were fou nd to express much more TGF-beta 1 and TGF-beta 2 mRNA than untreated PEC. Second, TGF-beta 2-treated PEC secreted large amounts of TGF-beta including its mature form. Third, addition of neutralizing anti-TGF-b eta 2 antibodies, but not neutralizing anti-TGF-beta 1 antibodies, res tored the ability of antigen-pulsed, TGF-beta 2-pretreated PEC to stim ulate DO11.10 T cells to secrete IL-2 and IFN-gamma. These results ind icate that antigen-presenting cells that encounter antigen in a TGF-be ta-enriched environment (e.g., in the eye) shift responding naive T ce lls toward Th2 responses by producing TGF-beta during antigen presenta tion.