Michael Lohoff

Interferon Regulatory Factor-1 Is Required for a T Helper 1 Immune Response In Vivo

The transcription factor interferon regulatory factor-1 (IRF-1) mediates the effects of IFN. No information exists on its role in lymphokine production. Protection against the intracellular pathogen Leishmania major depends on a Th1 response. Here, we show that CD4+ T cells from Leishmania-infected mice lacking one (+/-) or both (-/-) alleles of the IRF-1 gene developed a profound, gene dose-dependent decrease in IFNgamma production. IRF-1(-/-) mice showed dramatically exacerbated Leishmaniasis. They produced increased Leishmania-specific IgG1 and IgE, and their CD4+ T cells produced increased IL-4, characteristics of the non-protective Th2 response. In cell transfer experiments, IRF-1(-/-) CD4+ T cells mounted normal Th1 responses. However, the ability of IRF-1(-/-) mice to produce IL-12 was severely compromised. Thus, IRF-1 is a determining factor for Th1 responses.

Lack of gastritis and of an adaptive immune response in interferon regulatory factor‐1‐deficient mice infected with Helicobacter pylori

To study the role of T cell responses in Helicobacter pylori gastritis, C57BL / 6 wild‐type and interferon regulatory factor‐1‐deficient (IRF‐1– / –) mice were infected with the mouse‐adapted H. pylori Sydney strain. Mice lacking the transcription factor IRF‐1 are defective in Th1 development and are therefore biased to mount a Th2‐type response. After 4 months of infection, C57BL / 6 mice developed severe gastritis and atrophy and mounted a Th1‐type response towards H. pylori. The Th1 response was abrogated in IRF‐1– / – mice. This defective Th1 response was associated with the total lack of gastritis and atrophy in IRF‐1– / – mice despite severe colonization with H. pylori. In addition, IRF‐1– / – mice did also not develop a Th2 reaction, since they failed to generate H. pylori‐specific antibodies and to produce IL‐4 in response to H. pylori antigens in vitro. Thus, the transcription factor IRF‐1 is necessary for the development of gastritis and atrophy in H. pylori‐infected wild‐type mice, suggesting a role of Th1 cells in the pathogenesis of H. pylori‐associated diseases.

Coexistence of Antigen-Specific TH1 and TH2 Cells in Genetically Susceptible BALB/c Mice Infected with Leishmania major*

CD4-positive T cell clones with specificity for the protozoan parasite Leishmania major (L. major) of both the protective TH1 and the disease-exacerbating TH2 subtype were isolated from a diseased L. major-infected mouse of the susceptible BALB/c strain. In addition, TH2 cells were isolated from the lesion-draining lymph nodes of an animal clinically healed nine months after sublethal irradiation and subsequent infection. Our data support the notion that the differential outcome of the disease in non-irradiated versus irradiated BALB/c mice reflects the regulation of the two CD4+ T cell subsets. These data also argue against the possibilities that: 1) TH2 cells and their precursors are totally eliminated by irradiation and that 2) TH2 cells are capable of completely hindering the expansion of TH1 cells in diseased animals.

Interferon regulatory factor-1 is necessary for a T helper 1 immune response in vivo

The transcription factor interferon regulatory factor-1 (IRF-1) mediates the effects of IFN. No information exists on its role in lymphokine production. Protection against the intracellular pathogen Leishmania major depends on a Th1 response. Here, we show that CD4+ T cells from Leishmania-infected mice lacking one (+/−) or both (−/−) alleles of the IRF-1 gene developed a profound, gene dose-dependent decrease in IFNγ production. IRF-1−/− mice showed dramatically exacerbated Leishmaniasis. They produced increased Leish- mania-specific IgG1 and IgE, and their CD4+ T cells produced increased IL-4, characteristics of the nonprotective Th2 response. In cell transfer experiments, IRF-1−/− CD4+ T cells mounted normal Th1 responses. However, the ability of IRF-1−/− mice to produce IL-12 was severely compromised. Thus, IRF-1 is a determining factor for Th1 responses.