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 activate CD4+ T suppressor-inducer cells and induce tolerance, we hypothesized that they differentially up-regulate T cell early activation genes 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-PCR revealed that both C-EC (Langerhans cells) and UV-EC (UV-Mph) induced 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 CD4+ lymphocytes expressed cell surface IL-2R alpha, which increased to 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 = 0.038). The addition of neutralizing anti-TGF-beta Abs to UV-EC-stimulated cultures 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 induced by UV-EC and C-EC were similar). Furthermore, costimulatory signals 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 (tolerization) compared with Langerhans cells (sensitization) is reflected as a novel mechanism of initial CD4+ T cell early activation gene expression characterized by TGF-beta-dependent deficient IL-2R alpha expression.
D000938:Antigen-Presenting Cells / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007801:Langerhans Cells / Q000528:radiation effects; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000502:physiology / Q000528:radiation effects*; D008297:Male; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000032:analysis* / Q000096:biosynthesis; D012867:Skin / Q000276:immunology / Q000528:radiation effects*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014466:Ultraviolet Rays
D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta