825 J. Exp. Med.  The R ockefeller University Press • 0022-1007/ 97/ 03/ 825/ 07 $2.00 Volume 185, Number 5, March 3, 1997 825–831 Selective Expression of an Interleukin-12 Receptor Component by Human T Helper 1 Cells By Lars R ogge,* Luisella Barberis-Maino,* Mauro Biffi,* N adia Passini,* David H. Presky, ‡ Ueli Gubler, ‡ and Francesco Sinigaglia * From *R oche Milano R icerche, I-20132 Milan, Italy; and ‡ Department of Inflammation/ Autoimmune Diseases, Hoffmann-La R oche Inc., N utley, N ew Jersey 07110 Summary Interleukin-12 (IL-12), a heterodimeric cytokine produced by activated monocytes and den- dritic cells, plays a crucial role in regulating interferon (IFN)-  production and in the genera- tion of IFN––producing T helper 1 (Th1) cells. Here we show that the IL-12 receptor (IL- 12R ) 2 subunit, a recently cloned binding and signal transducing component of the IL-12R, is expressed on human Th1 but not Th2 clones and is induced during differentiation of human naive cells along the Th1 but not the Th2 pathway. IL-12 and type I but not type II interferons induce expression of the IL-12R 2 chain during in vitro T cell differentiation after antigen re- ceptor triggering. The selective expression and regulation of the IL-12R 2 subunit may help to understand the basis of Th1/ Th2 differentiation and may provide therapeutic options for al- tering the Th1/ Th2 balance in several immuno-pathological conditions such as autoimmune diseases and allergies. C D4 + T helper cells can be divided into three major subsets termed Th1, Th2, and Th0, based on the pat- tern of lymphokines they produce. Th1 cells produce IFN-  and predominantly promote cell-mediated immune re- sponses, whereas Th2 cells, which produce IL-4, IL-5, and IL-13, provide help for some B cell responses. IL-4 in par- ticular is the major inducer of B cell switching to IgE pro- duction (1), and therefore plays a crucial role in allergic re- actions involving IgE and mast cells. Th cells producing cytokines typical of both Th1 and Th2 clones have also been described in both the murine and human system, and they have been named Th0 (2). The differential develop- ment of these subsets is a major determinant of the out- come of physiological, as well as pathological, immune re- sponses including autoimmune, allergic, and infectious diseases (3, 4). Thus, understanding the mechanisms under- lying Th cell differentiation is essential for therapeutic ma- nipulation of the cytokine phenotype in disease conditions. Differentiation towards the Th1 or Th2 phenotype has been shown to be directed by exogenous cytokines present at the time of antigen exposure. IL-4 promotes Th2 develop- ment (5, 6), whereas IL-12 produced by APCs is a potent inducer of Th1 cells (7–9). Consistent with the necessity of IL-12 for induction of Th1 cell differentiation is the find- ing that IL-12 p40 -/ - mice are defective in IFN-  produc- tion and almost completely lack the ability to generate a Th1 response (10). Conversely, knockout of the IL-4 gene resulted in deficient Th2 responses (11, 12). Furthermore, the crucial role of IL-12 and IL-4 signaling in the differen- tiation of Th subsets has been analyzed more recently in mice deficient in the signal transducers and activators of transcription 6 and 4 (Stat6 and Stat4) 1 . These proteins are thought to mediate functional responses to IL-4 and IL-12, respectively. Stat6-deficient T lymphocytes fail to differen- tiate into Th2 cells in response to IL-4 (13–15), and the analysis of Stat4 -/ - T cells revealed an impaired production of IFN-  upon antigen triggering, indicative of a defect in Th1 differentiation (16, 17). In the present paper, we have studied IL-12 signaling and IL-12 receptor expression and regulation during differ- entiation of human naive T cells into the Th1 and the Th2 subsets. As previously reported in the murine system, IL-12 induces tyrosine phosphorylation of the transcription factor Stat4 in human Th1, but not Th2 cells. IL-12–dependent signaling in human Th1 cells correlates with the selective ex- pression of the transcripts encoding the signaling component of the IL-12 receptor (IL-12R ) 2 and with the presence of high affinity IL-12 binding sites selectively on Th1 cells. IL-12R 2 transcripts, which were absent in naive T cells, were found as early as 24 h after mitogen stimulation. IL-12 and type I but not type II IFNs induce expression of IL-12R 2 mR NAs, whereas IL-12R 2 transcripts could not be detected in cells stimulated in the presence of IL-4. The se- lective expression and regulation of the IL-12 receptor 2 1 A bbreviations used in this paper: IL-12R , IL-12 receptor; Stat, signal trans- ducers and activators of transcription. Downloaded from http://rupress.org/jem/article-pdf/185/5/825/1110828/5433.pdf by guest on 16 June 2022