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IFN- Mediates the Death of Th1 Cells in a Paracrine Manner¹

Kathryn E. Foulds^*, Masashi J. Rotte^*, Michael A. Paley^*, Babu Singh^*, Daniel C. Douek, Brenna J. Hill, John J. O’Shea, Wendy T. Watford, Robert A. Seder^2,* and Chang-You Wu

^* Cellular Immunology Section, and Human Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, and Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; and Department of Immunology, Zhongshan Medical School University, GuangZhou, China

Th1 cells have different capacities to develop into memory cells based on their production of IFN-. In this study, the mechanism by which a homogenous population of IFN--producing CD4 T cells was eliminated in vivo was assessed. When such cells were transferred into naive mice and activated with Ag, a striking decrease in the frequency of cells in the spleen and lung was observed. However, administration of neutralizing anti-IFN- Ab at the time of Ag challenge largely prevented the elimination of such cells. To determine whether IFN- was mediating its effects directly and/or indirectly, the ability of IFN- to effectively signal in such cells was assessed in vitro. Indeed, there was reduced phosphorylation of STAT1 in response to IFN- as well as markedly reduced expression of the IFN-R β-chain. Furthermore, transfer of such cells into IFN-R-deficient mice limited their death following activation with Ag. Together, these data suggest that IFN- acts in a paracrine manner to mediate the death of activated IFN--producing Th1 cells. In contrast to Ag stimulation, administration of CpG alone resulted in the elimination of Th1 cells in IFN-R^–/– mice. These results show that in response to Ag stimulation, the death of IFN--producing effector Th1 cells is controlled in an IFN--dependent manner, whereas in response to innate activation, the death of IFN--producing Th1 cells can occur through an IFN--independent pathway. Collectively, these data show the multiple mechanisms by which Th1 effector cells are efficiently eliminated in vivo.

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¹ This work is supported in part by grants from the National Key Basic Research Program of China (2007CB512404 to C.Y.W.) and the National Natural Science Foundation of China (30321004 to C.Y.W.).

² Address correspondence and reprint requests to Dr. Robert A. Seder, Cellular Immunology Section, Vaccine Research Center, National Institutes of Health, 40 Convent Drive, Room 3512, Bethesda, MD 20892. E-mail address: rseder{at}mail.nih.gov

³ Abbreviations used in this paper: Tg, transgenic; Tx; treatment.