B7-CD28 interaction promotes proliferation and survival but suppresses differentiation of CD4-CD8- T cells in the thymus.
Costimulatory molecules play critical roles in the induction and effector function of T cells. More recent studies reveal that costimulatory molecules enhance clonal deletion of autoreactive T cells as well as generation and homeostasis of the CD25(+)CD4(+) regulatory T cells. However, it is unclear whether the costimulatory molecules play any role in the proliferation and differentiation of T cells before they acquire MHC-restricted TCR. In this study, we report that targeted mutations of B7-1 and B7-2 substantially reduce the proliferation and survival of CD4(-)CD8(-) (double-negative (DN)) T cells in the thymus. Perhaps as a result of reduced proliferation, the accumulation of RAG-2 protein in the DN thymocytes is increased in B7-deficient mice, which may explain the increased expression of TCR gene and accelerated transition of CD25(+)CD44(-) (DN3) to CD25(-)CD44(-) (DN4) stage. Qualitatively similar, but quantitatively less striking effects were observed in mice with a targeted mutation of CD28, but not CTLA4. Taken together, our results demonstrate that the development of DN in the thymus is subject to modulation by the B7-CD28 costimulatory pathway.
Division of Cancer Immunology, Department of Pathology, Ohio State University Medical Center and Comprehensive Cancer Center, Columbus, OH 43210, USA.
Xincheng
X
Zheng
Jian-Xin
JX
Gao
Xing
X
Chang
Yin
Y
Wang
Yan
Y
Liu
Jing
J
Wen
Huiming
H
Zhang
Jian
J
Zhang
Yang
Y
Liu
Pan
P
Zheng
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051940:B7-2 Antigen; D015153:Blotting, Western; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D019672:Genes, T-Cell Receptor / Q000276:immunology; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497965:Cd86 protein, mouse; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2