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IFN‐γ Decreases CTL Generation by Limiting IL‐2 Production: A Feedback Loop Controlling Effector Cell Production
Author(s) -
Hidalgo Luis G.,
Urmson Joan,
Halloran Philip F.
Publication year - 2005
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2005.00761.x
Subject(s) - ctl* , cd8 , cytotoxic t cell , effector , interleukin 2 , immunology , biology , cytokine , medicine , microbiology and biotechnology , immune system , in vitro , biochemistry
IFN‐γ is produced by cytotoxic T lymphocytes (CTL) but can also decrease CTL generation. We used IFN‐γ‐R1‐deficient (GRKO) and IFN‐γ‐deficient (GKO) mice to study the effects of IFN‐γ 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‐γ 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‐γ 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‐γ that limits IL‐2 production which in turn limits CTL generation.