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*
Department of Immunology, Guy’s, King’s, and St. Thomas’s School of Medicine, Kings College, London, United Kingdom; and
Section of Allergy and Clinical Immunology, Department of Medicine, Yale University School of Medicine, New Haven, CT 06510
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-
-/-,
and OVA257–264-specific V
2V
5 TCR-transgenic mice, we
have identified the key steps involved. OVA-specific
IFN--/- CD8 T cells inhibited IgE responses equivalent
to wild-type CD8 T cells (up to 98% suppression), indicating that CD8
T cell-derived IFN- was not required. However, OVA-specific CD8 T
cells could not inhibit IgE in IFN--/- recipients
unless reconstituted with naive, wild-type CD4 T cells, suggesting that
CD4 T cell-derived IFN- did play a role. Transfer of either Tc1 or
Tc2 V2V5 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
OVA257–264-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--independent process that
subsequently induces Th1 and inhibits Th2 cells. Th1 cell IFN- 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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