Abstract
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.
Highlights
Tumor necrosis factor-alpha (TNF) is a pleiotropic cytokine involved in the initiation and orchestration of inflammation and immunity[1]
To examine the role of TNF-TNFR2 interaction in the development of pathogenic CD4 effector T cells (Teffs) in an autoimmune setting, the experimental colitis model induced by transfer of naïve CD4 T cells into lymphopenic Rag 1−/− mice was utilized
The colons in Rag 1−/− mice transferred with TNFR2-deficient naive CD4 T cells were markedly longer than that in mice transferred with WT naive CD4 T cells (p < 0.05, Fig. 1C,D, p < 0.05)
Summary
Tumor necrosis factor-alpha (TNF) is a pleiotropic cytokine involved in the initiation and orchestration of inflammation and immunity[1]. We have shown that TNFR2 was constitutively expressed by Tregs and TNF-TNFR2 interaction preferentially activated and expanded naturally occurring CD4+ Foxp3+ regulatory T cells (Tregs)[5,6,7,8] These surprising findings prompted other investigators to suggest that TNFR2 mediated the immunosuppressive effect of TNF, and TNFR2 agonists might provide effective treatments for autoimmunity[9]. In addition to being critical in promoting Treg activity, TNFR2 signaling is likely to play a role in the development of more pathogenic CD4 effector cells and may contribute to the inflammatory pathogenesis of CD4 cell-mediated autoimmunity. Further clarification of this possibility would help devise more effective and safer specific TNF receptor targeting treatment. In addition to its pivotal role in Tregs, TNFR2 is critical for the function of Teffs and may represent a therapeutic target in CD4 T cell-mediated autoimmune inflammation
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