TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis.
There is now compelling evidence that TNFR2 is constitutively expressed on CD4(+) Foxp3(+) regulatory T cells (Tregs) and TNF-TNFR2 interaction is critical for the activation, expansion and functional stability of Tregs. However, we showed that the expression of TNFR2 was also up-regulated on CD4(+) Foxp3(-) effector T cells (Teffs) upon TCR stimulation. In order to define the role of TNFR2 in the pathogenic CD4 T cells, we compared the effect of transferred naïve CD4 cells from WT mice and TNFR2(-/-) mice into Rag 1(-/-) recipients. Transfer of TNFR2-deficient Teff cells failed to induce full-fledged colitis, unlike WT Teffs. This was due to defective proliferative expansion of TNFR2-deficient Teff cells in the lymphopenic mice, as well as their reduced capacity to express proinflammatory Th1 cytokine on a per cell basis. In vitro, the proliferative response of TNFR2 deficient naïve CD4 cells to anti-CD3 stimulation was markedly decreased as compared with that of WT naïve CD4 cells. The hypoproliferative response of TNFR2-deficient Teff cells to TCR stimulation was associated with an increased ratio of p100/p52, providing a mechanistic basis for our findings. Therefore, this study clearly indicates that TNFR2 is important for the proliferative expansion of pathogenic Teff cells.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China.|Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.
Xin
X
Chen
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.
Yingjie
Y
Nie
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.|School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China.
Haitao
H
Xiao
School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China.
Zhaoxiang
Z
Bian
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.
Anthony J
AJ
Scarzello
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.
Na-Young
NY
Song
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.
Anna L
AL
Trivett
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.
De
Yang
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.
Joost J
JJ
Oppenheim
D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D049109:Cell Proliferation; D003092:Colitis / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism; D007249:Inflammation; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
D017252:CD3 Complex; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; D011948:Receptors, Antigen, T-Cell; D047889:Receptors, Tumor Necrosis Factor, Type II; C064658:RAG-1 protein; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse