A nonclassical MHC class I molecule restricts CTL-mediated rejection of a syngeneic melanoma tumor.
Although CTL and polymorphic, classical MHC class I molecules have well defined roles in the immune response against tumors, little is currently known regarding the participation of nonpolymorphic, nonclassical MHC class I in antitumor immunity. Using an MHC class I-deficient melanoma as a model tumor, we demonstrate that Q9, a murine MHC class Ib molecule from the Qa-2 family, expressed on the surface of tumor cells, protects syngeneic hosts from melanoma outgrowth. Q9-mediated protective immunity is lost or greatly diminished in mice deficient in CTL, including beta(2)-microglobulin knockout (KO), CD8 KO, and SCID mice. In contrast, the Q9 antitumor effects are not detectably suppressed in CD4 KO mice with decreased Th cell activity. Killing by antitumor CTL in vitro is Q9 specific and can be blocked by anti-Q9 and anti-CD8 Abs. The adaptive Q9-restricted CTL response leads to immunological memory, because mice that resist the initial tumor challenge reject subsequent challenges with less immunogenic tumor variants and show expansion of CD8(+) T cell populations with an activated/memory CD44(high) phenotype. Collectively, these studies demonstrate that a MHC class Ib molecule can serve as a restriction element for antitumor CTL and mediate protective immune responses in a syngeneic setting.
Chiang
Eugene Y
EY
Center for Immunology, Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Stroynowski
Iwona
I
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D000818:Animals; D045744:Cell Line, Tumor; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000502:physiology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D007156:Immunologic Memory / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009368:Neoplasm Transplantation / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014185:Transplantation, Isogeneic
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; C448919:MHC Ib Qa-2 antigen; C489516:Tap2 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor