Document Detail

An obligate cell-intrinsic function for CD28 in Tregs.
MedLine Citation:
PMID:  23281398     Owner:  NLM     Status:  MEDLINE    
Tregs expressing the transcription factor FOXP3 are critical for immune homeostasis. The costimulatory molecule CD28 is required for optimal activation and function of naive T cells; however, its role in Treg function has been difficult to dissect, as CD28 is required for thymic Treg development, and blockade of CD28-ligand interactions has confounding effects in trans on nonregulatory cells. To address this question, we created Treg-specific Cd28 conditional knockout mice. Despite the presence of normal numbers of FOXP3+ cells, these animals accumulated large numbers of activated T cells, developed severe autoimmunity that primarily affected the skin and lungs, and failed to appropriately resolve induced experimental allergic encephalomyelitis. This in vivo functional impairment was accompanied by dampened expression of CTLA-4, PD-1, and CCR6. Disease occurrence was not due to subversion of Cd28-deficient Tregs into pathogenic cells, as complementation with normal Tregs prevented disease occurrence. Interestingly, in these "competitive" environments, Cd28-deficient Tregs exhibited a pronounced proliferative/survival disadvantage. These data demonstrate clear postmaturational roles for CD28 in FOXP3+ Tregs and provide mechanisms which we believe to be novel to explain how interruption of CD28-ligand interactions may enhance immune responses independent of effects on thymic development or on other cell types.
Ruan Zhang; Alexandria Huynh; Gregory Whitcher; Jihoon Chang; Jonathan S Maltzman; Laurence A Turka
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-02
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2013-07-16    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  580-93     Citation Subset:  AIM; IM    
Transplant Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
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MeSH Terms
Adoptive Transfer
Antigens, CD28 / deficiency,  genetics,  metabolism*
Bacterial Proteins / genetics,  metabolism
Encephalomyelitis, Autoimmune, Experimental / immunology,  metabolism,  pathology
Forkhead Transcription Factors / genetics,  metabolism
Luminescent Proteins / genetics,  metabolism
Lymphocyte Activation
Lymphoid Tissue / cytology,  immunology,  metabolism
Mice, Knockout
Mice, Transgenic
Recombinant Proteins / genetics,  metabolism
T-Lymphocytes, Regulatory / immunology*,  metabolism
Grant Support
Reg. No./Substance:
0/Antigens, CD28; 0/Bacterial Proteins; 0/Forkhead Transcription Factors; 0/Foxp3 protein, mouse; 0/Luminescent Proteins; 0/Recombinant Proteins; 0/yellow fluorescent protein, Bacteria

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