"Default" generation of neonatal regulatory T cells.
CD4(+)Foxp3(+) regulatory T (Treg) cells were shown to control all aspects of immune responses. How these Treg cells develop is not fully defined, especially in neonates during development of the immune system. We studied the induction of Treg cells from neonatal T cells with various TCR stimulatory conditions, because TCR stimulation is required for Treg cell generation. Independent of the types of TCR stimulus and without the addition of exogenous TGF-beta, up to 70% of neonatal CD4(+)Foxp3(-) T cells became CD4(+)Foxp3(+) Treg cells, whereas generally <10% of adult CD4(+)Foxp3(-) T cells became CD4(+)Foxp3(+) Treg cells under the same conditions. These neonatal Treg cells exert suppressive function and display relatively stable Foxp3 expression. Importantly, this ability of Treg cell generation gradually diminishes within 2 wk of birth. Consistent with in vitro findings, the in vivo i.p. injection of anti-CD3 mAb to stimulate T cells also resulted in a >3-fold increase in Treg cells in neonates but not in adults. Furthermore, neonatal or adult Foxp3(-) T cells were adoptively transferred into Rag1(-/-) mice. Twelve days later, the frequency of CD4(+)Foxp3(+) T cells converted from neonatal cells was 6-fold higher than that converted from adult cells. Taken together, neonatal CD4(+) T cells have an intrinsic "default" mechanism to become Treg cells in response to TCR stimulations. This finding provides intriguing implications about neonatal immunity, Treg cell generation, and tolerance establishment early in life.
Wang
Guohua
G
Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, OH 43614, USA.
Miyahara
Yoshihiro
Y
Guo
Zhiyong
Z
Khattar
Mithun
M
Stepkowski
Stanislaw M
SM
Chen
Wenhao
W
D019264:Adoptive Transfer; D000818:Animals; D000831:Animals, Newborn; D015704:CD4 Antigens / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055550:Protein Stability; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell