Egress of mature murine regulatory T cells from the thymus requires RelA.
The mechanism of egress of mature regulatory T cells (Tregs) from the thymus to the periphery remains enigmatic, as does the nature of those factors expressed in the thymic environment. In this study, we examined the fate of thymic Tregs in TNF-α/RelA double-knockout (TA-KO) mice, because TA-KO mice retain a Treg population in the thymus but have only a small Treg population at the periphery. Transplantation of whole TA-KO thymus to under the kidney capsule of Rag1-null mice failed to induce the production of donor-derived splenic Tregs expressing neuropilin-1, which is reported to be a marker of naturally occurring Tregs, indicating that TA-KO thymic Tregs either do not leave the thymus or are lost at the periphery. We next transplanted enriched TA-KO thymic Tregs to the peripheries of TA-KO mice and traced mouse survival. Transplantation of TA-KO thymic Tregs rescued the lethality in TA-KO mice, demonstrating that TA-KO thymic Tregs remained functional at the periphery. The TA-KO thymic Treg population had highly demethylated CpG motifs in the foxp3 locus, indicating that the cells were arrested at a late mature stage. Also, the population included a large subpopulation of Tregs expressing IL-7Rα, which is a possible marker of late-stage mature Tregs. Finally, TA-KO fetal liver chimeric mice developed a neuropilin-1(+) splenic Treg population from TA-KO cells, suggesting that Treg arrest was caused by a lack of RelA in the thymic environment. Taken together, these results suggest that egress of mature Tregs from the thymus depends on RelA in the thymic environment.
Technology and Development Team for BioSignal Program, RIKEN BioResource Center, Ibaraki 305-0074, Japan; Department of Immunology, Kochi Medical School, Kochi University, Kochi 783-8505, Japan;
Taro
T
Fukazawa
Experimental Animal Division, RIKEN BioResource Center, Ibaraki 305-0074, Japan; and.
Noriko
N
Hiraiwa
Center for Innovative and Translational Medicine, Kochi Medical School, Kochi University, Kochi 783-8505, Japan.
Takeshi
T
Umemura
Technology and Development Team for BioSignal Program, RIKEN BioResource Center, Ibaraki 305-0074, Japan;
Setsuko
S
Mise-Omata
Technology and Development Team for BioSignal Program, RIKEN BioResource Center, Ibaraki 305-0074, Japan;
Yuichi
Y
Obata
Technology and Development Team for BioSignal Program, RIKEN BioResource Center, Ibaraki 305-0074, Japan; godtak@gmail.com.
Takahiro
T
Doi
D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D018899:CpG Islands; D019175:DNA Methylation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D056426:Genetic Loci; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*
D015415:Biomarkers; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020395:Receptors, Interleukin-7; D051996:Transcription Factor RelA; C415350:interleukin-7 receptor, alpha chain