CD4⁺ Th-APC with acquired peptide/MHC class I and II complexes stimulate type 1 helper CD4⁺ and central memory CD8⁺ T cell responses

T cell-T cell Ag presentation is increasingly attracting attention. We previously showed that the in vitro OVA-pulsed dendritic cell (DC _OVA)-activated CD4⁺ Th cells acquired OVA peptide/MHC (pMHC) class I and costimulatory molecules such as CD54 and CD80 from DC _OVA and acted as CD4⁺ Th-APC capable of stimulating OVA-specific CD8⁺ CTL responses. In this study, we further applied the OVA-specific TCR-transgenic OT I and OT II mice with deficiency of various cytokines or costimulatory molecule genes useful for studying the molecular mechanisms underlying in Th-APC's stimulatory effect. We demonstrated that DC_OVA-stimulated OT II CD4⁺ Th-APC also acquired costimulatory molecules such as CD40, OX40L, and 4-1BBL and the functional pMHC II complexes by DC_OVA activation. CD4⁺ Th-APC with acquired pMHC II and I were capable of stimulating CD4⁺ Th1 and central memory CD8⁺44⁺CD62L^highIL-7R ⁺ T cell responses leading to antitumor immunity against OVA-expressing mouse B16 melanoma. Their stimulatory effect on CD8⁺ CTL responses and antitumor immunity is mediated by IL-2 secretion, CD40L, and CD80 signaling and is specifically targeted to CD8⁺ T cells in vivo via acquired pMHC I. In addition, CD4⁺ Th-APC expressing OVA-specific TCR, FasL, and perforin were able to kill DC_OVA and neighboring Th-APC expressing endogenous and acquired pMHC II. Taken together, we show that CD4⁺ Th-APC can modulate immune responses by stimulating CD4 ⁺ Th1 and central memory CD8⁺ T cell responses and eliminating DC_OVA and neighboring Th-APC. Therefore, our findings may have great impacts in not only the antitumor immunity, but also the regulatory T cell-dependent immune tolerance in vivo.