Soluble antigen and CD40 triggering are sufficient to induce primary and memory cytotoxic T cells

The signals directing induction of tolerance rather than immunity are large ly unknown. The CD8 T cell response to soluble Ags generally results in del etional tolerance following transient, costimulation-dependent activation. We demonstrated that CD40 signaling reversed the outcome of this response, Adoptive transfer of OVA-specific CD8 T cells followed by soluble OVA immun ization resulted in induction of lytic activity and optimal clonal expansio n only when CD40 was triggered via an agonistic mAb, Activation of CD8 T ce lls by CD40 signaling was indirect, because CD40 expression by host cells w as required. CD40 signaling along with soluble Ag immunization also induced expansion of secondary lymphoid and intestinal mucosal endogenous OVA-spec ific CD8 T cells as detected by MHC tetramer reactivity. When CD40 activati on was included, long-lived secondary lymphoid and mucosal memory CD8 cells were generated from adoptively transferred and endogenous CD8 T cells, Muc osal and peripheral CDS memory cells exhibited constitutive Ag-specific lyt ic activity, with mucosal memory cells being 10-fold more lytic than spleni c or lymph node memory cells. These results demonstrated that CD40 signalin g during a response to a poorly immunogenic soluble Ag aas necessary and su fficient for CTL and memory T cell induction.