CD8 T cells inhibit IgE via dendritic cell IL-12 induction that promotes Th1 T cell counter-regulation.
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 Valpha2Vbeta5 TCR-transgenic mice, we have identified the key steps involved. OVA-specific 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 Tc1 or Tc2 Valpha2Vbeta5 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 1 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.
Thomas
Matthew J
MJ
Department of Immunology, Guy's, King's, and St. Thomas's School of Medicine, Kings College, Rayne Institute, 123 Coldharbour Lane, London, SE5 9NU, United Kingdom.
Noble
Alistair
A
Sawicka
Ela
E
Askenase
Philip W
PW
Kemeny
David M
DM
D019264:Adoptive Transfer; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D004527:Egg Proteins / Q000276:immunology; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D004527:Egg Proteins; C110366:OVA-8; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018664:Interleukin-12; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010047:Ovalbumin