Absence of CTLA-4 lowers the activation threshold of primed CD8+ TCR-transgenic T cells: lack of correlation with Src homology domain 2-containing protein tyrosine phosphatase.
To examine the role of CTLA-4 in controlling Ag-specific CD8(+) T cell activation, TCR-transgenic/CTLA-4 wild-type or -deficient mice were generated in a recombination-activating gene 2-deficient background. Naive T cells from these mice responded comparably whether or not CTLA-4 was expressed. In contrast, primed T cells responded more vigorously if they lacked CTLA-4 expression. We took advantage of the difference between naive and primed T cell responses to approach the mechanism of CTLA-4 function. Single-cell analyses demonstrated that a greater fraction of CTLA-4-deficient cells responded to a fixed dose of Ag compared with CTLA-4-expressing cells, whereas the magnitude of response per cell was comparable. A shift in the dose-response curve to APCs was also observed such that fewer APCs were required to activate CTLA-4-deficient T cells to produce intracellular IFN-gamma and to proliferate. These results suggest that CTLA-4 controls the threshold of productive TCR signaling. Biochemical analysis comparing stimulated naive and primed TCR-transgenic cells revealed no obvious differences in expression of total CTLA-4, tyrosine-phosphorylated CTLA-4, and associated Src homology domain 2-containing protein tyrosine phosphatase. Thus, the biochemical mechanism explaining the differential inhibitory effect of CTLA-4 on naive and primed CD8(+) T cells remains unclear.
Gajewski
T F
TF
Department of Pathology, University of Chicago, Chicago, IL 60637, USA. tgajewsk@medicine.bsd.uchicago.edu
Fallarino
F
F
Fields
P E
PE
Rivas
F
F
Alegre
M L
ML
D000069594:Abatacept; D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D007114:Immunization; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D007399:Interphase / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured; D018909:src Homology Domains / Q000235:genetics / Q000276:immunology*
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D004268:DNA-Binding Proteins; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; C064655:V(D)J recombination activating protein 2; D000069594:Abatacept; D017027:Protein Tyrosine Phosphatases