title: IL-12 is required for mTOR regulation of memory CTLs during viral infection.
abstract: The induction of functional memory cytotoxic T lymphocytes (CTLs) is a major goal of vaccination against intracellular pathogens. Interleukin (IL)-12 is critical for the generation of memory CTLs, and inhibition of mammalian target of rapamycin (mTOR) by rapamycin can effectively enhance the memory CTL response. Yet, the role of IL-12 in mTOR's regulation of memory CTL is unknown. Here we hypothesized that the immunostimulatory effects of mTOR on memory CTLs requires IL-12 signaling. Our results revealed that rapamycin increased the generation of memory CTLs in vaccinia virus infection, and this enhancement was dependent upon the IL-12 signal. Furthermore, IL-12 receptor deficiency diminished the secondary expansion of rapamycin-regulated memory and resultant secondary memory CTLs were abolished. Rapamycin enhanced IL-12 signaling by upregulating IL-12 receptor β2 expression and signal transducer and activator of transcription factor 4 phosphorylation in CTLs during early infection. In addition, rapamycin continually suppressed T-bet expression in both wild-type and IL-12 receptor knockout CTLs. These results indicate an essential role for IL-12 in the regulation of memory CTLs by mTOR and highlight the importance of considering the interplay between cytokines and adjuvants during vaccine design.
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Garcia
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Mattson
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Smyth
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Xiao
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology* / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053707:Receptors, Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D050797:STAT4 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D020123:Sirolimus / Q000276:immunology / Q000494:pharmacology; D020825:T-Box Domain Proteins / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism; D014615:Vaccinia / Q000235:genetics / Q000276:immunology* / Q000821:virology; D014616:Vaccinia virus / Q000276:immunology* / Q000502:physiology; D000098815:T-bet Transcription Factor
chemical_list: D007166:Immunosuppressive Agents; D007376:Interleukin-2; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus