Recent thymic origin, differentiation, and turnover of regulatory T cells

Nicholas H. E. Mabarrack, Nicole L. Turner and Graham Mayrhofer¹

School of Molecular and Biomedical Science, University of Adelaide, Australia

¹ Correspondence: School of Molecular and Biomedical Science, University of Adelaide, North Terrace, Adelaide, SA 5005, Australia. E-mail: graham.mayrhofer{at}adelaide.edu.au

Regulatory CD4⁺ T cells (T_reg) are essential to maintain self-tolerance.Release of natural T_reg from the thymus is believed to commencesoon after birth, but it is unclear how many are produced by"conversion" in the periphery, whether numbers are maintainedafter puberty by general homeostatic mechanisms that regulatelymphocyte numbers, or whether significant numbers are producedby the involuted thymus. To address the origin of T_reg in normaladult rats, we focused on recent thymus emigrants (RTE). Approximately30% of CD4⁺CD25⁺forkhead box p3 (Foxp3)⁺ T_reg expressed markersassociated with RTE. Following thymectomy, numbers of cellsexpressing these markers fell by 80% within 30 days. Furthermore,although only $~$ 5% of CD4⁺ single-positive thymocytes expressedFoxp3 within 24 h after intrathymic injection of FITC, morethan 30% of the labeled CD4⁺ RTE were Foxp3⁺, suggesting thatsome RTE may acquire Foxp3 in the periphery. Thus, some RTEmay acquire Foxp3 rapidly after emigration from the thymus.T_reg are dividing rapidly with apparent half-lives of $~$ 18 daysand $~$ 7 days for the CD4⁺CD25⁺Foxp3⁺ and CD4⁺CD25^–Foxp3⁺subsets, respectively. The apparently slower turnover of CD4⁺CD25⁺Foxp3⁺cells is a result of CD4⁺CD25⁺Foxp3⁺ $->$ CD4⁺CD25^–Foxp3⁺conversion, with no loss of regulatory function. Taken together,the data suggest that T_reg in adults are relatively short-livedand that their numbers are maintained by rapid cell divisionand continuous replenishment from the thymus.

Key Words: emigrant • anergy • thymus • thymectomy • Foxp3 • CD25