Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, Immunology, EXPRESSION, CD4(+)CD25(+), COSTIMULATION, HOMEOSTASIS, SURVIVAL, INTERLEUKIN-2, MUTATIONS, GENE, MICE, Animals, Autoimmunity, CD28 Antigens, Cell Differentiation, Cell Lineage, Cell Survival, Clonal Selection, Antigen-Mediated, Forkhead Transcription Factors, Gene Expression Regulation, Developmental, Homeostasis, Mice, Mice, Transgenic, Signal Transduction, T-Lymphocyte Subsets, T-Lymphocytes, Regulatory, 0601 Biochemistry and Cell Biology, 1107 Immunology, 3101 Biochemistry and cell biology, 3204 Immunology

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.Immunology and Cell Biology advance online publication, 23 December 2014; doi:10.1038/icb.2014.108.