Journal
JOURNAL OF IMMUNOLOGY
Volume 168, Issue 1, Pages 216-223Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.168.1.216
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Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P50HL056389, P01HL056389] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R21AI043371] Funding Source: NIH RePORTER
- NHLBI NIH HHS [HL-56389] Funding Source: Medline
- NIAID NIH HHS [AI-43371] Funding Source: Medline
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Th1 and Th2 cells are counterinhibitory; their balance determines allergic sensitization. We show here that CD8 T cell subsets break these rules as both T cytotoxic (Tc)1 and Tc2 cells promote Th1 over Th2 immunity. Using IL-12(-/-), IFN-gamma (-/-), and OVA(257-264)-specific V alpha 2V beta5 TCR-transgenic mice, we have identified the key steps involved. OVA-specifie IFN-gamma (-/-) CD8 T cells inhibited IgE responses equivalent to wild-type CD8 T cells (up to 98% suppression), indicating that CD8 T cell-derived IFN-gamma was not required. However, OVA-specific CD8 T cells could not inhibit IgE in IFN-gamma (-/-) recipients unless reconstituted with naive, wild-type CD4 T cells, suggesting that CD4 T cell-derived IFN-gamma did play a role. Transfer of either Tel or Tc2 V alpha 2V beta5 TCR-transgenic CD8 T cells inhibited IgE and OVA-specific Th2 cells while promoting OVA-specific Th1 cell responses, suggesting a potential role for a type I inducing cytokine such as IL-12. CD8 T cells were shown to induce IL-12 in OVA(257-264)-pulsed dendritic cells (DC) in vitro. Furthermore, CD8 T cells were unable to inhibit IgE responses in IL-12(-/-) recipients without the addition of naive, wild-type DC, thus demonstrating a pivotal role for IL-12 in this mechanism. These data reveal a mechanism of IgE regulation in which CD8 T cells induce DC IL-12 by an IFN-gamma -independent process that subsequently induces Th1 and inhibits Th2 cells. Th1 cell IFN-gamma is the final step that inhibits B cell IgE class switching. This demonstrates a novel regulatory network through which CD8 T cells inhibit allergic sensitization.
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