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CD4⁺ Th-APC with Acquired Peptide/MHC Class I and II Complexes Stimulate Type 1 Helper CD4⁺ and Central Memory CD8⁺ T Cell Responses¹

Channakeshava Sokke Umeshappa^*, Hui Huang^*, Yufeng Xie^*, Yangdou Wei, Sean J. Mulligan, Yulin Deng and Jim Xiang^2,*,

^* Research Unit, Research Division, Saskatchewan Cancer Agency and Department of Oncology, Department of Immunology, Department of Biology, and Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; and School of Life Sciences and Technology, Beijing Institute of Technology, Beijing, China

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by Research Grant MOP 79415 from the Canadian Institute for Health Research.

² Address correspondence and reprint requests to Dr. Jim Xiang, Saskatoon Cancer Center, 20 Campus Drive, Saskatoon, Saskatchewan S7N 4H4, Canada. E-mail address: jim.xiang{at}saskcancer.ca

³ Abbreviations used in this paper: DC_OVA, OVA-pulsed dendritic cell; _CMCTL, central memory CTL; _EMCTL, effector memory CTL; ECD, energy-coupled dye; pMHC, peptide/MHC; CMA, concanamycin A; KO, knockout; Tm, memory T; Tr, regulatory T.