alexa TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T. cell phenotype in the inflammatory environment.
Diabetes & Endocrinology

Diabetes & Endocrinology

Journal of Diabetes & Metabolism

Author(s): Chen X, Wu X, Zhou Q, Howard OM, Netea MG,

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Abstract Several lines of evidence indicate the instability of CD4(+)Foxp3(+) regulatory T cells (Tregs). We have therefore investigated means of promoting the stability of Tregs. In this study, we found that the proportion of Tregs in mouse strains deficient in TNFR2 or its ligands was reduced in the thymus and peripheral lymphoid tissues, suggesting a potential role of TNFR2 in promoting the sustained expression of Foxp3. We observed that upon in vitro activation with plate-bound anti-CD3 Ab and soluble anti-CD28 Ab, Foxp3 expression by highly purified mouse Tregs was markedly downregulated. Importantly, TNF partially abrogated this effect of TCR stimulation and stabilized Foxp3 expression. This effect of TNF was blocked by anti-TNFR2 Ab, but not by anti-TNFR1 Ab. Furthermore, TNF was not able to maintain Foxp3 expression by TNFR2-deficient Tregs. In a mouse colitis model induced by transfer of naive CD4 cells into Rag1(-/-) mice, the disease could be inhibited by cotransfer of wild-type Tregs, but not by cotransfer of TNFR2-deficient Tregs. Furthermore, in the lamina propria of the colitis model, most wild-type Tregs maintained Foxp3 expression. In contrast, an increased number of TNFR2-deficient Tregs lost Foxp3 expression. Thus, our data clearly show that TNFR2 is critical for the phenotypic and functional stability of Tregs in the inflammatory environment. This effect of TNF should be taken into account when designing future therapy of autoimmunity and graft-versus-host disease by using TNF inhibitors.
This article was published in J Immunol and referenced in Journal of Diabetes & Metabolism

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