Journal
IMMUNOLOGY AND CELL BIOLOGY
Volume 93, Issue 4, Pages 417-423Publisher
WILEY
DOI: 10.1038/icb.2014.108
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Funding
- FWO [92819]
- German Research Foundation [SFB738]
- Biotechnology and Biological Sciences Research Council
- Biotechnology and Biological Sciences Research Council [BBS/E/B/000C0409, BBS/E/B/000C0407] Funding Source: researchfish
- BBSRC [BBS/E/B/000C0407, BBS/E/B/000C0409] Funding Source: UKRI
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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.
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