c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells.
During thymopoiesis, a unique program of gene expression promotes the development of CD4 regulatory T (T reg) cells. Although Foxp3 maintains a pattern of gene expression necessary for T reg cell function, other transcription factors are emerging as important determinants of T reg cell development. We show that the NF-kappaB transcription factor c-Rel is highly expressed in thymic T reg cells and that in c-rel(-/-) mice, thymic T reg cell numbers are markedly reduced as a result of a T cell-intrinsic defect that is manifest during thymocyte development. Although c-Rel is not essential for TGF-beta conversion of peripheral CD4(+)CD25(-) T cells into CD4(+)Foxp3(+) cells, it is required for optimal homeostatic expansion of peripheral T reg cells. Despite a lower number of peripheral T reg cells in c-rel(-/-) mice, the residual peripheral c-rel(-/-) T reg cells express normal levels of Foxp3, display a pattern of cell surface markers and gene expression similar to those of wild-type T reg cells, and effectively suppress effector T cell function in culture and in vivo. Collectively, our results indicate that c-Rel is important for both the thymic development and peripheral homeostatic proliferation of T reg cells.
Isomura
Iwao
I
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
Palmer
Stephanie
S
Grumont
Raelene J
RJ
Bunting
Karen
K
Hoyne
Gerard
G
Wilkinson
Nancy
N
Banerjee
Ashish
A
Proietto
Anna
A
Gugasyan
Raffi
R
Wu
Li
L
Li
Wu
W
McNally
Alice
A
Steptoe
Raymond J
RJ
Thomas
Ranjeny
R
Shannon
M Frances
MF
Gerondakis
Steve
S
D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival; D003092:Colitis / Q000517:prevention & control; D051858:Forkhead Transcription Factors / Q000502:physiology*; D019254:Genes, bcl-2; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D038041:Lymphopoiesis; D051379:Mice; D008810:Mice, Inbred C57BL; D020569:Proto-Oncogene Proteins c-rel / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020569:Proto-Oncogene Proteins c-rel