SUPPRESSOR T-CELL-ACTIVATING MACROPHAGES IN ULTRAVIOLET-IRRADIATED HUMAN SKIN INDUCE A NOVEL, TGF-BETA-DEPENDENT FORM OF T-CELL ACTIVATION CHARACTERIZED BY DEFICIENT IL-2R-ALPHA EXPRESSION

Because UV-induced epidermal macrophages (UV-Mph) preferentially activ ate CD4(+) T suppressor-inducer cells and induce tolerance, we hypothe sized that they differentially up-regulate T cell early activation gen es compared with constitutive epidermal APC, Langerhans cells. We used epidermal cells from UV-exposed (UV-EC) and control (C-EC) human skin to stimulate allogeneic CD4(+) T lymphocytes. Reverse transcriptase-P CR revealed that both C-EC (Langerhans cells) and UV-EC (UV-Mph) induc ed 10(3)- to 10(6)-fold increases in IL-2 mRNA. However, while T cells stimulated by C-EC for 48 h showed a greater than 10(3)-fold increase in IL-2R alpha mRNA, those stimulated by UV-EC did not (n = 5, p = 0. 004). Flow cytometry demonstrated that 4.1 +/- 2.3% of unstimulated CD 4(+) lymphocytes expressed cell surface lL-2R alpha, which increased t o 15.7 +/- 1.8% upon stimulation by C-EC for 48 h, but stimulation by UV-EC failed to increase the IL-2R alpha(+) population (n = 3, p = 0.0 38). The addition of neutralizing anti-TGF-P Abs to UV-EC-stimulated c ultures restored CD4(+) cell surface IL-2R alpha expression to 12.9 +/ - 0.2%. CD4(+) T cell activation by UV-Mph is distinct from previously described models of tolerance such as Th2 activation (IFN-gamma mRNA was induced and IL-4 mRNA was not) and Th1 anergy (IL-2 mRNA levels in duced by UV-EC and C-EC were similar). Furthermore, costimulatory sign als were provided by UV-Mph; CTLA4-Ig and LFA-3-Ig fusion proteins and Abs to CD2, LFA-3, LFA-1, and ICAM-1 inhibited UV-Mph-induced T cell proliferation. Thus, the altered immune outcome induced by UV-Mph (tol erization) compared with Langerhans cells (sensitization) is reflected as a novel mechanism of initial CD4(+) T cell early activation gene e xpression characterized by TGF-beta dependent deficient IL-2R alpha ex pression.