title: Differential effects of IL-12 on Tregs and non-Treg T cells: roles of IFN-γ, IL-2 and IL-2R.
abstract: Complex interactions between effector T cells and Foxp3(+) regulatory T cells (Treg) contribute to clinical outcomes in cancer, and autoimmune and infectious diseases. Previous work showed that IL-12 reversed Treg-mediated suppression of CD4(+)Foxp3(-) T cell (Tconv) proliferation. We and others have also shown that Tregs express T-bet and IFN-γ at sites of Th1 inflammation and that IL-12 induces IFN-γ production by Tregs in vitro. To investigate whether loss of immunosuppression occurs when IFN-γ is expressed by Tregs we treated mouse lymphocyte cultures with IL-12. IFN-γ expression did not decrease the ability of Tregs to suppress Tconv proliferation. Rather, IL-12 treatment decreased Treg frequency and Foxp3 levels in Tregs. We further showed that IL-12 increased IL-2R expression on Tconv and CD8 T cells, diminished its expression on Tregs and decreased IL-2 production by Tconv and CD8 T cells. Together, these IL-12 mediated changes favored the outgrowth of non-Tregs. Additionally, we showed that treatment with a second cytokine, IL-27, decreased IL-2 expression without augmenting Tconv and CD8 T cell proliferation. Notably, IL-27 only slightly modified levels of IL-2R on non-Treg T cells. Together, these results show that IL-12 has multiple effects that modify the balance between Tregs and non-Tregs and support an important role for relative levels of IL-2R but not for IFN-γ expression in IL-12-mediated reversal of Treg immunosuppression.
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Jingxian
authors.initials: J
authors.lastname: Zhao
authors.forename: Jincun
authors.initials: J
authors.lastname: Zhao
authors.forename: Stanley
authors.initials: S
authors.lastname: Perlman
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology; D018664:Interleukin-12 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000235:genetics* / Q000276:immunology; D007378:Interleukins / Q000494:pharmacology; D051379:Mice; D009928:Organ Specificity; D015375:Receptors, Interleukin-2 / Q000235:genetics* / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C486767:Il27 protein, mouse; D007376:Interleukin-2; D007378:Interleukins; D015375:Receptors, Interleukin-2; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma