The plasticity of regulatory T cell function.
Regulatory T cells (T(regs)) can suppress a wide variety of cell types, in diverse organ sites and inflammatory conditions. Whereas T(regs) possess multiple suppressive mechanisms, the number required for maximal function is unclear. Furthermore, whether any interrelationship or cross-regulatory mechanisms exist to orchestrate and control their utilization is unknown. In this study, we assessed the functional capacity of T(regs) lacking the ability to secrete both IL-10 and IL-35, which individually are required for maximal T(reg) activity. Surprisingly, IL-10/IL-35 double-deficient T(regs) were fully functional in vitro and in vivo. Loss of IL-10 and IL-35 was compensated for by a concurrent increase in cathepsin E (Ctse) expression, enhanced TRAIL (Tnfsf10) expression, and soluble TRAIL release, rendering IL-10/IL-35 double-deficient T(regs) functionally dependent on TRAIL in vitro and in vivo. Lastly, whereas C57BL/6 T(regs) are normally IL-10/IL-35 dependent, BALB/c T(regs), which express high levels of cathepsin E and enhanced TRAIL expression, are partially TRAIL dependent by default. These data reveal that cross-regulatory pathways exist that control the utilization of suppressive mechanisms, thereby providing T(reg) functional plasticity.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
Meenu R
MR
Pillai
Lauren W
LW
Collison
Xiaohua
X
Wang
David
D
Finkelstein
Jerold E
JE
Rehg
Kelli
K
Boyd
Andrea L
AL
Szymczak-Workman
Teresa
T
Doggett
Thomas S
TS
Griffith
Thomas A
TA
Ferguson
Dario A A
DA
Vignali
D000818:Animals; D020059:Cathepsin E / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D016753:Interleukin-10 / Q000172:deficiency / Q000378:metabolism; D007378:Interleukins / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology
D007378:Interleukins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; C532417:interleukin-35, human; D016753:Interleukin-10; D020059:Cathepsin E