CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism.
A tumor-specific CD8+ T cell response was studied using adoptive transfer of OT-I TCR transgenic cells. Upon i.p. challenge with E.G7 tumor, OT-I cells undergo CD4+ T cell-independent expansion at the tumor site and develop lytic function. Before tumor elimination, however, they leave the peritoneal cavity (PC) and appear in the LN and spleen where they exhibit "split anergy" and cannot further proliferate to antigen. Administering anti-CTLA-4 mAb early caused sustained OT-1 expansion in the PC, and late administration caused the OT-I cells to return to the PC and further expand; in both cases, tumor was controlled. These effects required CD4+ T cells and IL-2 and appear to result from reversal of the nonresponsive state of the CD8+ T cells.
Shrikant
P
P
Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA.
Khoruts
A
A
Mescher
M F
MF
D000069594:Abatacept; D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D002634:Chemotaxis, Leukocyte; D017635:Clonal Anergy; D004334:Drug Administration Schedule; D007108:Immune Tolerance / Q000276:immunology*; D018796:Immunoconjugates; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D010529:Peritoneal Cavity / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013945:Thymoma / Q000276:immunology / Q000473:pathology; D013953:Thymus Neoplasms / Q000276:immunology / Q000473:pathology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007376:Interleukin-2; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D000069594:Abatacept; D010047:Ovalbumin