title: Tumor necrosis factor receptor 2-dependent homeostasis of regulatory T cells as a player in TNF-induced experimental metastasis.
abstract: The cytokine tumor necrosis factor (TNF) has pleiotropic functions both in normal physiology and disease. TNF signals by the virtue of two cell surface receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Exogenous TNF promotes experimental metastasis in some models, yet the underlying mechanisms are poorly understood. To study the contribution of host TNFR1 and TNFR2 on tumor cell progression and metastasis, we employed a syngeneic B16F10 melanoma mouse model of lung metastasis combined with in vivo bioluminescence imaging. Treatment of tumor-bearing mice with recombinant human TNF resulted in a significant increase in tumor burden and metastatic foci. This correlated with an increase in pulmonary regulatory CD4(+)/Foxp3(+) T cells. TNF caused an expansion of regulatory T (Treg) cells in vitro in a TNFR2-dependent manner. To assess the contribution of immune cell expression of endogenous TNF and its two receptors on B16F10 metastasis, we generated bone marrow chimeras by reconstituting wild-type mice with bone marrow from different knockout mice. Loss of either TNF or TNFR2 on immune cells resulted in decreased B16F10 metastasis and lower numbers of Treg cells within the lungs of these animals. Selective depletion of Treg cells attenuated metastasis even in conjunction with TNF treatment. We propose a novel mechanism in which TNF activates TNFR2 on Treg cells and thereby expands this immunosuppressive immune cell population. Loss of either TNF or TNFR2 prevents the accumulation of Treg cells and results in a less tolerogenic environment, enabling the immune system to control B16F10 tumor metastasis and growth.
authors: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
authors: Martin
authors: M
authors: Chopra
authors: Simone S
authors: SS
authors: Riedel
authors: Marlene
authors: M
authors: Biehl
authors: Stefanie
authors: S
authors: Krieger
authors: Viktoria
authors: V
authors: von Krosigk
authors: Carina A
authors: CA
authors: Bäuerlein
authors: Christian
authors: C
authors: Brede
authors: Ana-Laura
authors: AL
authors: Jordan Garrote
authors: Sabrina
authors: S
authors: Kraus
authors: Viktoria
authors: V
authors: Schäfer
authors: Miriam
authors: M
authors: Ritz
authors: Katharina
authors: K
authors: Mattenheimer
authors: Axelle
authors: A
authors: Degla
authors: Anja
authors: A
authors: Mottok
authors: Hermann
authors: H
authors: Einsele
authors: Harald
authors: H
authors: Wajant
authors: Andreas
authors: A
authors: Beilhack
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D008545:Melanoma; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C521469:micp75TNFR protein, mouse