In vitro generated Th17 cells support the expansion and phenotypic stability of CD4(+)Foxp3(+) regulatory T cells in vivo.
CD4(+) T cells stimulate immune responses through distinct patterns of cytokine produced by Th1, Th2 or Th17 cells, or inhibit immune responses through Foxp3-expressing regulatory T cells (Tregs). Paradoxically, effector T cells were recently shown to activate Tregs, however, it remains unclear which Th subset is responsible for this effect. In this study, we found that Th17 cells expressed the highest levels of TNF among in vitro generated Th subsets, and most potently promoted expansion and stabilized Foxp3 expression by Tregs when co-transferred into Rag1(-/-) mice. Both TNF and IL-2 produced by Th17 cells contributed to this effect. The stimulatory effect of Th17 cells on Tregs was largely abolished when co-transferred with TNFR2-deficient Tregs. Furthermore, Tregs deficient in TNFR2 also supported a much lower production of IL-17A and TNF expression by co-transferred Th17 cells. Thus, our data indicate that the TNF-TNFR2 pathway plays a crucial role in the reciprocal stimulatory effect of Th17 cells and Tregs. This bidirectional interaction should be taken into account when designing therapy targeting Th17 cells, Tregs, TNF and TNFR2.
Laboratory of Molecular Immunoregulation, Cancer Inflammation Program, Center for Cancer Research, NCI, Frederick, MD 21702, United States.
Qiong
Q
Zhou
Ya
Y
Hu
O M Zack
OM
Howard
Joost J
JJ
Oppenheim
Xin
X
Chen
D019264:Adoptive Transfer; D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000096:biosynthesis / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*
D015704:CD4 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C098680:Il17a protein, mouse; D020381:Interleukin-17; D007376:Interleukin-2; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha
FoxP3; IL-2; KI; KO; Regulatory T cell; TNF; TNFR2; TNFR2 Fc fusion protein; TNFR2-Fc; Teffs; Th17; Tregs; effector T cells; forkhead box P3; knock in; knock out; nCD4; naïve CD4 cells; regulatory T cells; tumor necrosis factor receptor type II