Unaltered negative selection and Treg development of self-reactive thymocytes in TCR transgenic Fyn-deficient mice.
The tyrosine kinase Fyn has been implicated as playing an important role in the generation of both stimulatory and inhibitory signaling events induced by TCR engagement. To assess the role of Fyn for antigen-driven negative selection and Treg development, which are both dependent on the strength and nature of TCR signaling, we generated mice that co-express the transgenes for OVA and the OT-II TCR, which recognizes a peptide from OVA. In mice expressing both transgenes, negative selection, Treg development in the thymus, and the number of Treg in the periphery were each unaffected by ablation of Fyn. Moreover, fyn(-/-) Treg were functional, as assessed in vitro. We further tested the role of Fyn for the adaptor function of c-Cbl, using mice containing a point mutation in c-Cbl that abolishes its E3 ubiquitin ligase function but maintains its adaptor function. The functional and signaling properties of this mutant c-Cbl were unaltered in fyn(-/-) thymocytes. Combined, these data indicate that Fyn was not required for the induction of central tolerance by negative selection, the adaptor protein role of c-Cbl, or the normal development and function of Treg.
Mamchak
Alusha A
AA
Department of Microbiology and Immunology, University of California, San Francisco, CA, USA.
Thien
Christine B F
CB
Dagger
Samantha A
SA
Lyandres
Julia
J
Jiang
Shuwei
S
Langdon
Wallace Y
WY
DeFranco
Anthony L
AL
D000818:Animals; D000941:Antigens / Q000276:immunology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*
D000941:Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; D050721:Proto-Oncogene Proteins c-cbl; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C493849:Cbl protein, mouse