Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses.
CTLA-4-deficient mice develop a fatal lymphoproliferative disorder, characterized by polyclonal expansion of peripheral lymphocytes. To examine the effect of restricting the CD4(+) TCR repertoire on the phenotype of CTLA-4-deficient mice and to assess the influence of CTLA-4 on peptide-specific CD4(+) T cell responses in vitro, an MHC class II-restricted T cell receptor (AND TCR) transgene was introduced into the CTLA-4(-/-) animals. The expression of the AND TCR transgene by CD4(+) T cells delays but does not prevent the lymphoproliferation in the CTLA-4(-/-) mice. The CD4(+) T cells become preferentially activated and expand. Interestingly, young AND TCR(+) CTLA-4(-/-) mice carrying a null mutation in the rag-1 gene remain healthy and the T cells maintain a naive phenotype until later in life. We demonstrate that CTLA-4 regulates the peptide-specific proliferative response generated by naive and previously activated AND TCR(+) RAG(-/-) T cells in vitro. The absence of CTLA-4 also augments the responder frequency of cytokine-secreting AND TCR(+) RAG(-/-) T cells. These results demonstrate that CTLA-4 is a key regulator of peptide-specific CD4(+) T cell responses and support the model that CTLA-4 plays a differential role in maintaining T cell homeostasis of CD4(+) vs. CD8(+) T cells.
Howard Hughes Medical Research Institute, Cancer Research Laboratory, Department of Molecular and Cellular Biology, University of California, Berkeley, CA 94720, USA.
C A
CA
Chambers
M S
MS
Kuhns
J P
JP
Allison
D000069594:Abatacept; D000818:Animals; 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; D002452:Cell Count; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D018796:Immunoconjugates; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000276:immunology; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D000949:Histocompatibility Antigens Class II; D018398:Homeodomain Proteins; D018796:Immunoconjugates; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; C064658:RAG-1 protein; D000069594:Abatacept