Neutrophils are professional phagocytes that migrate early, in high number, to the infection sites. Our study has analyzed how neutrophils cross-present antigens and influence CD8 ؉ T-cell responses. By using highly purified neutrophils from peritoneal exudates and bone marrow, we have shown that neutrophils crosspresent ovalbumin to a CD8 ؉ T-cell hybridoma and to naive CD8 ؉ T cells from OT1 transgenic mice. Cross-presentation by neutrophils was TAP and proteasome dependent and was as efficient as in macrophages. Moreover, it actually occurred earlier than in professional antigenpresenting cells. Peritoneal exudate neutrophils from mice injected intraperitoneally with ovalbumin also cross-presented ovalbumin, proving that neutrophils take up and present exogenous antigens into major histocompatibility complex I (MHC I) molecules in vivo. We then evaluated the in vivo influence of antigen crosspresentation by neutrophils on CD8 ؉ Tcell response using 2-microglobulindeficient mice transferred with OT1 CD8 ؉ T cells and injected with ovalbuminpulsed neutrophils. Four days after neutrophil injection, OT1 cells proliferated and expressed effector functions (IFN-␥ production and cytolysis). They also responded efficiently to a rechallenge with ovalbumin-pulsed dendritic cells in CFA. These data are the first demonstration that neutrophils cross-prime CD8 ؉ T cells in vivo and suggest that they may constitute, together with professional antigenpresenting cells, an attractive target to induce cytotoxic T cells in vaccines.
IntroductionAlthough it was originally thought that peptides presented into major histocompatibility complex I (MHC I) molecules to CD8 ϩ T cells derived exclusively from endogenous proteins, it is now admitted that, under certain circumstances, professional antigenpresenting cells (APCs; dendritic cells [DCs] and macrophages) can present some exogenous antigens in the MHC I molecules. 1,2 This process, called antigen cross-presentation, can occur by 2 different mechanisms. One is dependent on the transporter associated with antigen processing (TAP) that includes proteasomedependent and -independent pathways, and the other one is TAP independent. 3 Due to their ability (1) to migrate from peripheral tissues to the lymph nodes, where they encounter recirculating naive T cells, and (2) to express high levels of costimulatory molecules, DCs are usually considered as the only APC able to prime naive T cells. 4,5 This property has recently been extended to murine macrophages. 6 Activated DCs can present some exogenous proteins to naive CD8 ϩ T cells and induce their differentiation into effector cytotoxic T cells (CTLs). This process, referred to as cross-priming, allows the in vivo generation of protective cytotoxic responses against microorganisms that do not infect DCs or that infect DCs but inhibit their properties. 7 Cross-priming by DCs has opened new perspectives in vaccines based on CTL induction. 7,8 In the absence of licensing, DCs stimulate an abortive response that leads to cross-tolerance...