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(high)IL-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.
Umeshappa
Channakeshava Sokke
CS
Research Unit, Research Division, Saskatchewan Cancer Agency and Department of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Huang
Hui
H
Xie
Yufeng
Y
Wei
Yangdou
Y
Mulligan
Sean J
SJ
Deng
Yulin
Y
Xiang
Jim
J
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D003601:Cytotoxicity Tests, Immunologic; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007156:Immunologic Memory; D019041:L-Selectin / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000502:physiology*; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D018960:Hyaluronan Receptors; D010446:Peptide Fragments; D020395:Receptors, Interleukin-7; D019041:L-Selectin