title: "Bystander polarization" of CD4+ T cells: activation with high-dose IL-2 renders naive T cells responsive to IL-12 and/or IL-18 in the absence of TCR ligation.
abstract: Responsiveness of CD4+ T cells to the IFN-gamma-inducing cytokines IL-12 and IL-18 is generally thought to be acquired only after stimulation via the TCR. We report herein that stimulation of naive CD4+ T cells with high-dose IL-2 (1000 U/ml) renders these cells responsive to IL-12 and/or IL-18 without a requirement for TCR ligation. Naive CD4+CD62L+ Tcells from normal C57BL/6 mice or from DO11.10/Rag2(-/- )OVA-specific TCR-transgenic mice secreted substantial amounts of IFN-gamma when stimulated concurrently with high-dose IL-2 plus IL-12 or IL-18. mRNA encoding both chains of the IL-12 and the IL-18 receptors was expressed by CD4+ T cells after stimulation with high-dose IL-2. Furthermore, anti-CD3-induced IL-12/IL-18 responsiveness was fully abrogated in the presence of cyclosporin A whereas IL-2-induced IL-12/IL-18 responsiveness was not, reminiscent of the previously reported IL-12+IL-18 innate pathway of T cell activation. Lastly, after stimulation with IL-2+IL-12, naive CD4+ T cells from DO11.10/Rag2(-/- )mice exhibited polarization towards a Th1 phenotype (high IFN-gamma but no IL-4) during secondary stimulation with immobilized anti-CD3. We have coined the term "bystander polarization" to describe this phenomenon and we speculate that bystander polarization of naive CD4+ T cells may occur in vivo during strong antigen-specific immune responses.
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, K1H 8M5, Canada.
authors.forename: Habiba
authors.initials: H
authors.lastname: Chakir
authors.forename: Debbie Ka Yee
authors.initials: DK
authors.lastname: Lam
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lemay
authors.forename: John R
authors.initials: JR
authors.lastname: Webb
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism
chemical_list: D020382:Interleukin-18; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D018664:Interleukin-12