Journal ArticleDOI
Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4
Paul Waterhouse,Josef M. Penninger,Emma Timms,Andrew Wakeham,Arda Shahinian,Kelvin P. Lee,Craig B. Thompson,Henrik Griesser,Tak W. Mak +8 more
TLDR
Although CTLA-4-deficient T cells proliferated spontaneously and strongly when stimulated through the T cell receptor, they were sensitive to cell death induced by cross-linking of the Fas receptor and by gamma irradiation, and is vital for the control of lymphocyte homeostasis.Abstract:
The role of the cell-surface molecule CTLA-4 in the regulation of T cell activation has been controversial. Here, lymph nodes and spleens of CTLA-4-deficient mice accumulated T cell blasts with up-regulated activation markers. These blast cells also infiltrated liver, heart, lung, and pancreas tissue, and amounts of serum immunoglobulin were elevated. The mice invariably became moribund by 3 to 4 weeks of age. Although CTLA-4-deficient T cells proliferated spontaneously and strongly when stimulated through the T cell receptor, they were sensitive to cell death induced by cross-linking of the Fas receptor and by gamma irradiation. Thus, CTLA-4 acts as a negative regulator of T cell activation and is vital for the control of lymphocyte homeostasis.read more
Citations
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Journal ArticleDOI
The blockade of immune checkpoints in cancer immunotherapy
TL;DR: Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
Journal ArticleDOI
Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3
Wanjun Chen,Wenwen Jin,Neil J. Hardegen,Ke Jian Lei,Li Li,Nancy J. Marinos,George McGrady,Sharon M. Wahl +7 more
TL;DR: Novel evidence is presented that conversion of naive peripheral CD4+CD25− T cells into anergic/suppressor cells that are CD25+, CD45RB−/low and intracellular CTLA-4+ can be achieved through costimulation with T cell receptors (TCRs) and transforming growth factor β (TGF-β).
Journal ArticleDOI
Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.
Gordon J. Freeman,Andrew J. Long,Yoshiko Iwai,Karen Bourque,Tatyana Chernova,Hiroyuki Nishimura,Lori Fitz,Nelly Malenkovich,Taku Okazaki,Michael C. Byrne,Heidi F. Horton,Lynette A. Fouser,Laura L. Carter,Vincent Ling,Michael R Bowman,Beatriz M. Carreno,Mary Collins,Clive Wood,Tasuku Honjo +18 more
TL;DR: It is reported here that the ligand of PD-1 (PD-L1), an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells, is a member of the B7 gene family.
Journal ArticleDOI
PD-1 and its ligands in tolerance and immunity
TL;DR: Current understanding of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential are discussed and an inhibitory bidirectional interaction between PD-L1 and B7-1 is discovered, revealing new ways the B7:CD28 family regulates T cell activation and tolerance.
Journal ArticleDOI
Enhancement of antitumor immunity by CTLA-4 blockade.
TL;DR: In vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors, and this rejection resulted in immunity to a secondary exposure to tumor cells, suggesting that blockade of the inhibitory effects of CTLA4 can allow for, and potentiate, effective immune responses against tumor cells.
References
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Journal ArticleDOI
Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease
Marcia M. Shull,Ilona Ormsby,Ann B. Kier,Sharon A. Pawlowski,Ronald J. Diebold,Moying Yin,Ruth D. Allen,Charles L. Sidman,Gabriele Proetzel,Dawn Calvin,Nikki Annunziata,Thomas Doetschman +11 more
TL;DR: TGF-β1-deficient mice may be valuable models for human immune and inflammatory disorders, including autoimmune diseases, transplant rejection and graft versus host reactions.
Journal ArticleDOI
Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis
Rie Watanabe-Fukunaga,Camilynn I. Brannan,Neal G. Copeland,Nancy A. Jenkins,Shigekazu Nagata +4 more
TL;DR: The Ipr mice develop lymphadenopathy and suffer from a systemic lupus erythematosus-like autoimmune disease, indicating an important role for Fas antigen in the negative selection of autoreactive T cells in the thymus.
Journal ArticleDOI
CTLA-4 can function as a negative regulator of T cell activation
Theresa L. Walunas,Deborah J. Lenschow,Christina Y. Bakker,Peter S. Linsley,Gordon J. Freeman,Jonathan Green,Craig B. Thompson,Craig B. Thompson,Jeffrey A. Bluestone +8 more
TL;DR: Results suggest that the MAb may obstruct the interaction of CTLA-4 with its natural ligand and block a negative signal, or directly signal T cells to down-regulate immune function.
Journal ArticleDOI
CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation.
TL;DR: It is shown here that the presence of low levels of B7-2 on freshly explanted T cells can partially inhibit T cell proliferation, and this inhibition is mediated by interactions with CTLA-4, which strongly suggests that the outcome of T cell antigen receptor stimulation is regulated by CD28 costimulatory signals, as well as inhibitory signals derived from CTla-4.
Journal ArticleDOI
Lethal effect of the anti-Fas antibody in mice
Jun Ogasawara,Rie Watanabe-Fukunaga,Masashi Adachi,Akio Matsuzawa,Tsutomu Kasugai,Yukihiko Kitamura,Naoto Itoh,Takashi Suda,Shigekazu Nagata +8 more
TL;DR: The findings suggest that the Fas antigen is important in programmed cell death in the liver, and may be involved in fulminant hepatitis in some cases.
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