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Discovery Research Department, Immunex Corporation, Seattle, WA 98101
Dendritic cells (DCs) are bone marrow-derived APCs that display
unique properties aimed at stimulating naive T cells. Several members
of the TNF/TNFR families have been implicated in T cell functions. In
this study, we examined the role that Ox40 costimulation might play on
the ability of DCs to regulate CD4+ and CD8+ T
cell responses in vivo. Administration of anti-mouse Ox40 mAb
enhanced the Th response induced by immunization with Ag-pulsed DCs,
and introduced a bias toward a Th1 immune response. However,
anti-Ox40 treatment enhanced the production of Th2 cytokines in
IFN-
-/- mice after immunization with Ag-pulsed DCs,
suggesting that the production of IFN- during the immune response
could interfere with the development of Th2 lymphocytes induced by DCs.
Coadministration of anti-Ox40 with DCs during Ag rechallenge
enhanced both Th1 and Th2 responses induced during a primary
immunization with DCs, and did not reverse an existing Th2 response.
This suggests that Ox40 costimulation amplifies an ongoing immune
response, regardless of Th differentiation potential. In an OVA-TCR
class II-restricted adoptive transfer system, anti-Ox40 treatment
greatly enhanced the level of cytokine secretion per Ag-specific
CD4+ T cell induced by immunization with DCs. In an OVA-TCR
class I-restricted adoptive transfer system, administration of
anti-Ox40 strongly enhanced expansion, IFN- secretion, and
cytotoxic activity of Ag-specific CD8+ T cells induced by
immunization with DCs. Thus, by enhancing immune responses induced by
DCs in vivo, the Ox40 pathway might be a target for immune intervention
in therapeutic settings that use DCs as Ag-delivery
vehicles.
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