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Promiscuous Foxp3-cre activity reveals a differential requirement for CD28 in Foxp3⁺ and Foxp3⁻ T cells.

Franckaert, Dean
; 
Dooley, James
; 
Roos, Evelyne
; 
Floess, Stefan
; 
Huehn, Jochen
; 
Luche, Herve
; 
Fehling, Hans Joerg
; 
Liston, Adrian
; 
Linterman, Michelle A
; 
Schlenner, Susan M
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2015-04
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Abstract
Costimulatory signals by CD28 are critical for thymic regulatory T-cell (Treg) development. To determine the functional relevance of CD28 for peripheral Treg post thymic selection, we crossed the widely used Forkhead box protein 3 (Foxp3)-CreYFP mice to mice bearing a conditional Cd28 allele. Treg-specific CD28 deficiency provoked a severe autoimmune syndrome as a result of a strong disadvantage in competitive fitness and proliferation of CD28-deficient Tregs. By contrast, Treg survival and lineage integrity were not affected by the lack of CD28. This data demonstrate that, even after the initial induction requirement, Treg maintain a higher dependency on CD28 signalling than conventional T cells for homeostasis. In addition, we found the Foxp3-CreYFP allele to be a hypomorph, with reduced Foxp3 protein levels. Furthermore, we report here the stochastic activity of the Foxp3-CreYFP allele in non-Tregs, sufficient to recombine some conditional alleles (including Cd28) but not others (including R26-RFP). This hypomorphism and 'leaky' expression of the Foxp3-CreYFP allele should be considered when analysing the conditionally mutated Treg.
Citation
Promiscuous Foxp3-cre activity reveals a differential requirement for CD28 in Foxp3⁺ and Foxp3⁻ T cells. 2015, 93 (4):417-23 Immunol. Cell Biol.
Affiliation
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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Journal
Immunology and cell biology
URI
http://hdl.handle.net/10033/600466
DOI
10.1038/icb.2014.108
PubMed ID
25533288
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Article
Language
en
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1440-1711
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publications of the research group experimentelle Immunologie (EXIM)