title: Inflammation enhances IL-2 driven differentiation of cytolytic CD4 T cells.
abstract: Cytolytic CD4 T cells (CD4 CTL) have been identified in vivo in response to viral infections; however, the factors necessary for driving the cytolytic phenotype have not been fully elucidated. Our previously published work suggests IL-2 may be the master regulator of perforin-mediated cytotoxicity in CD4 effectors. To further dissect the role of IL-2 in CD4 CTL generation, T cell receptor transgenic mice deficient in the ability to produce IL-2 or the high affinity IL-2 receptor (IL-2Rα, CD25) were used. Increasing concentrations of IL-2 were necessary to drive perforin (Prf) expression and maximal cytotoxicity. Granzyme B (GrB) expression and killing correlated with STAT5 activation and CD25 expression in vitro, suggesting that signaling through the high affinity IL-2R is critical for full cytotoxicity. IL-2 signaling was also necessary in vivo for inducing the Th1 phenotype and IFN-γ expression in CD4 T cells during influenza A (IAV) infection. In addition, GrB expression, as measured by mean fluorescent intensity, was decreased in CD25 deficient cells; however, the frequency of CD4 cells expressing GrB was unchanged. Similarly, analysis of cytolytic markers such as CD107a/b and Eomesodermin indicate high IL-2Rα expression is not necessary to drive the CD4 CTL phenotype during IAV infection. Thus, inflammatory signals induced by viral infection may overcome the need for strong IL-2 signals in driving cytotoxicity in CD4 cells.
authors.affiliation: School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America ; Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
authors.forename: Aspen M
authors.initials: AM
authors.lastname: Workman
authors.affiliation: Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
authors.forename: Ashley K
authors.initials: AK
authors.lastname: Jacobs
authors.affiliation: School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Vogel
authors.affiliation: School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America ; Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
authors.forename: Shirley
authors.initials: S
authors.lastname: Condon
authors.affiliation: School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America ; Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Brown
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D053804:Granzymes / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007376:Interleukin-2 / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D054353:Perforin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D047428:Protein Kinase Inhibitors; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D054353:Perforin; D053616:Janus Kinase 3; D053804:Granzymes