title: IL-12 is required for anti-OX40-mediated CD4 T cell survival.
abstract: Engagement of OX40 greatly improves CD4 T cell function and survival. Previously, we showed that both OX40 engagement and CTLA-4 blockade led to enhanced CD4 T cell expansion, but only OX40 signaling increased survival. To identify pathways associated with OX40-mediated survival, the gene expression of Ag-activated CD4 T cells isolated from mice treated with anti-OX40 and -CTLA-4 was compared. This comparison revealed a potential role for IL-12 through increased expression of the IL-12R-signaling subunit (IL-12Rbeta2) on T cells activated 3 days previously with Ag and anti-OX40. The temporal expression of IL-12Rbeta2 on OX40-stimulated CD4 T cells was tightly regulated and peaked approximately 4-6 days after initial activation/expansion, but before the beginning of T cell contraction. IL-12 signaling, during this window of IL-12Rbeta2 expression, was required for enhanced T cell survival and survival was associated with STAT4-specific signaling. The findings from these observations were exploited in several different mouse tumor models where we found that the combination of anti-OX40 and IL-12 showed synergistic therapeutic efficacy. These results may lead to the elucidation of the molecular pathways involved with CD4 T cell survival that contribute to improved memory, and understanding of these pathways could lead to greater efficacy of immune stimulatory Abs in tumor-bearing individuals.
authors.affiliation: Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213, USA.
authors.forename: Carl E
authors.initials: CE
authors.lastname: Ruby
authors.forename: Ryan
authors.initials: R
authors.lastname: Montler
authors.forename: Rongxui
authors.initials: R
authors.lastname: Zheng
authors.forename: Suyu
authors.initials: S
authors.lastname: Shu
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology; D005260:Female; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053765:Interleukin-12 Subunit p35 / Q000172:deficiency / Q000235:genetics; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000276:immunology; D053707:Receptors, Interleukin-12 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D053262:Receptors, OX40 / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; C508443:Il12rb2 protein, mouse; D053765:Interleukin-12 Subunit p35; D053707:Receptors, Interleukin-12; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; D018664:Interleukin-12