Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi Cells.
CD4(+)Foxp3(+) regulatory T (Treg) cells originate primarily from thymic differentiation, but conversion of mature T lymphocytes to Foxp3 positivity can be elicited by several means, including in vitro activation in the presence of TGF-beta. Retinoic acid (RA) increases TGF-beta-induced expression of Foxp3, through unknown molecular mechanisms. We showed here that, rather than enhancing TGF-beta signaling directly in naive CD4(+) T cells, RA negatively regulated an accompanying population of CD4(+) T cells with a CD44(hi) memory and effector phenotype. These memory cells actively inhibited the TGF-beta-induced conversion of naive CD4(+) T cells through the synthesis of a set of cytokines (IL-4, IL-21, IFN-gamma) whose expression was coordinately curtailed by RA. This indirect effect was evident in vivo and required the expression of the RA receptor alpha. Thus, cytokine-producing CD44(hi) cells actively restrain TGF-beta-mediated Foxp3 expression in naive T cells, and this balance can be shifted or fine-tuned by RA.
Hill
Jonathan A
JA
Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Hall
Jason A
JA
Sun
Cheng-Ming
CM
Cai
Qi
Q
Ghyselinck
Norbert
N
Chambon
Pierre
P
Belkaid
Yasmine
Y
Mathis
Diane
D
Benoist
Christophe
C
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006706:Homeostasis; D018960:Hyaluronan Receptors / Q000032:analysis; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018168:Receptors, Retinoic Acid / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*; D000098546:Interleukin-21
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018960:Hyaluronan Receptors; D007378:Interleukins; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D014212:Tretinoin; D007371:Interferon-gamma; D000098546:Interleukin-21