IFN-γ Decreases CTL Generation by Limiting IL-2 Production: A Feedback Loop Controlling Effector Cell Production

Abstract

IFN-c is produced by cytotoxic T lymphocytes (CTL)but can also decrease CTL generation. We used IFN-c -R1-deficient (GRKO) and IFN-c -deficient (GKO) mice to study the effects of IFN-c 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-c 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-c 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-c that limits IL-2 production which in turn limits CTL generation.

Reduced Neointima Formation After Arterial Injury in CD4−/− Mice Is Mediated by CD8 + CD28 hi T Cells

“…IL‐2 is a known regulator of T‐cell function. Relevantly to our studies, exogenous IL‐2 enhanced CD8 + cytolytic activity . Thus, increased splenic IL‐2 mRNA expression in the steady state of CD4−/− mice compared with WT mice is in agreement with the reported role of IL‐2 bioavailability in enhancing cytolytic activity.…”

Liver Repopulation by Transplanted Hepatocytes and Risk of Hepatocellular Carcinoma

“…Second, both IL-2 and IFN-␥ double k/o mice reject cardiac allografts faster than wild-type mice (44). Third, IFN-␥ limits the proliferation of IL-2 producing CD4 ϩ T cells, which in turn limit CD8 ϩ CTL generation (48). CD4 ϩ T cell depletion prevents rejection in wild type but not in IFN-␥ k/o, indicating a CD8 ϩ T cell mechanism mediates rejection in the absence of IFN-␥ (45).…”

IFN-γ Dictates Allograft Fate via Opposing Effects on the Graft and on Recipient CD8 T Cell Responses

“…In particular, the results from studies describing the influence of IFNγ on CD8 T cell responses are often confounded by the possibility of indirect actions of IFNγ via other cell types within the system (13-15). Indeed, IFNγ is known to skew CD4 T helper cell responses toward the T h 1 phenotype, thereby indirectly boosting CD8-mediated immune responses (16).…”