Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells.
Although TNF is a major proinflammatory cytokine, increasing evidence indicates that TNF also has immunosuppressive feedback effects. We have demonstrated in this study that, in both resting and activated states, mouse peripheral CD4(+)CD25(+) T regulatory cells (Tregs) expressed remarkably higher surface levels of TNFR2 than CD4(+)CD25(-) T effector cells (Teffs). In cocultures of Tregs and Teffs, inhibition of proliferation of Teffs by Tregs was initially transiently abrogated by exposure to TNF, but longer exposure to TNF restored suppressive effects. Cytokine production by Teffs remained continually suppressed by Tregs. The profound anergy of Tregs in response to TCR stimulation was overcome by TNF, which expanded the Treg population. Furthermore, in synergy with IL-2, TNF expanded Tregs even more markedly up-regulated expression of CD25 and FoxP3 and phosphorylation of STAT5, and enhanced the suppressive activity of Tregs. Unlike TNF, IL-1beta and IL-6 did not up-regulate FoxP3-expressing Tregs. Furthermore, the number of Tregs increased in wild-type mice, but not in TNFR2(-/-) mice following sublethal cecal ligation and puncture. Depletion of Tregs significantly decreased mortality following cecal ligation and puncture. Thus, the stimulatory effect of TNF on Tregs resembles the reported costimulatory effects of TNF on Teffs, but is even more pronounced because of the higher expression of TNFR2 by Tregs. Moreover, our study suggests that the slower response of Tregs than Teffs to TNF results in delayed immunosuppressive feedback effects.
Chen
Xin
X
Laboratory of Molecular Immunoregulation, Basic Research Program, SAIC-Frederick, National Cancer Institute, Frederick, MD 21702, USA. chenxin@mail.nih.gov
Bäumel
Monika
M
Männel
Daniela N
DN
Howard
O M Zack
OM
Oppenheim
Joost J
JJ
D000818:Animals; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology; D018920:Coculture Techniques; D025461:Feedback, Physiological / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000172:deficiency; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*
D053645:Interleukin-2 Receptor alpha Subunit; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha