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

Year
2014
Type(s)
Author(s)
Dean Franckaert, James Dooley, Evelyne Roos, Stefan Floess, Jochen Huehn, Herve Luche, Hans Joerg Fehling, Adrian Liston, Michelle A Linterman and Susan M Schlenner
Source
Immunology & Cell Biology
Url
https://www.nature.com/icb/journal/v93/n4/full/icb2014108a.html
BibTeX
BibTeX

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.