title: IFN-gamma decreases CTL generation by limiting IL-2 production: A feedback loop controlling effector cell production.
abstract: IFN-gamma is produced by cytotoxic T lymphocytes (CTL) but can also decrease CTL generation. We used IFN-gamma-R1-deficient (GRKO) and IFN-gamma-deficient (GKO) mice to study the effects of IFN-gamma in MLC on the generation of CTL activity and CTL number, IL-2 production and cell proliferation. CTL activity was increased in MLC when GRKO responders or GKO stimulators and responders were used, compared to wild-type (WT) MLC. The number of cells displaying the CTL phenotype (CD3+, CD8+, CD25+) was also increased, accompanied by increased IL-2 production and proliferation. Combinations of WT or GRKO CD4+ T cells with WT or GRKO CD8+ T cells as responders showed that IFN-gamma mostly affects CD4+ T cells to limit CTL generation. Intracellular staining indicated that IL-2 production was largely by CD4+ T cells. Moreover, addition of IL-2 to WT responders mimicked GKO CTL generation and activity, whereas neutralizing IL-2 decreased CTL activity in GRKO and WT responders. Thus IFN-gamma reduces CTL generation in alloimmune responses largely by limiting proliferation of IL-2 producing CD4+ T cells. This creates a feedback loop in which effectors produce IFN-gamma that limits IL-2 production which in turn limits CTL generation.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Luis G
authors.initials: LG
authors.lastname: Hidalgo
authors.forename: Joan
authors.initials: J
authors.lastname: Urmson
authors.forename: Philip F
authors.initials: PF
authors.lastname: Halloran
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D025461:Feedback, Physiological / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000172:deficiency / Q000378:metabolism*; D007376:Interleukin-2 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D017471:Receptors, Interferon / Q000172:deficiency; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D007376:Interleukin-2; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor