Antigen specificity acquisition of adoptive CD4+ regulatory T cells via acquired peptide-MHC class I complexes.
The Ag-specific CD4(+) regulatory T (Tr) cells play an important role in immune suppression in autoimmune diseases and antitumor immunity. However, the molecular mechanism for Ag-specificity acquisition of adoptive CD4(+) Tr cells is unclear. In this study, we generated IL-10- and IFN-gamma-expressing type 1 CD4(+) Tr (Tr1) cells by stimulation of transgenic OT II mouse-derived naive CD4(+) T cells with IL-10-expressing adenovirus (AdV(IL-10))-transfected and OVA-pulsed dendritic cells (DC(OVA/IL-10)). We demonstrated that both in vitro and in vivo DC(OVA/IL-10)-stimulated CD4(+) Tr1 cells acquired OVA peptide MHC class (pMHC) I which targets CD4(+) Tr1 cells suppressive effect via an IL-10-mediated mechanism onto CD8(+) T cells, leading to an enhanced suppression of DC(OVA)-induced CD8(+) T cell responses and antitumor immunity against OVA-expressing murine B16 melanoma cells by approximately 700% relative to analogous CD4(+) Tr1 cells without acquired pMHC I. Interestingly, the nonspecific CD4(+)25(+) Tr cells can also become OVA Ag specific and more immunosuppressive in inhibition of OVA-specific CD8(+) T cell responses and antitumor immunity after uptake of DC(OVA)-released exosomal pMHC I complexes. Taken together, the Ag-specificity acquisition of CD4(+) Tr cells via acquiring DC's pMHC I may be an important mean in augmenting CD4(+) Tr cell suppression.
Hao
Siguo
S
Department of Oncology, Research Unit, Saskatchewan Cancer Agency, College of Medicine, Saskatoon, Saskatchewan, Canada.
Yuan
Jinying
J
Xu
Shulin
S
Munegowda
Manjunatha Ankathatti
MA
Deng
Yulin
Y
Gordon
John
J
Xing
Zhou
Z
Xiang
Jim
J
D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D045142:Cross-Priming / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology / Q000378:metabolism*; D006182:H-Y Antigen / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D018448:Models, Immunological; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D011506:Proteins / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D013997:Time Factors
D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D006182:H-Y Antigen; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D011506:Proteins; C102450:Uty protein, mouse