title: Progranulin promotes tumour necrosis factor-induced proliferation of suppressive mouse CD4⁺ Foxp3⁺ regulatory T cells.
abstract: Progranulin (PGRN) is a pleiotropic growth factor with immunosuppressive properties. Recently, it was reported that PGRN was an antagonist of tumour necrosis factor (TNF) receptors, preferentially for TNFR2. However, we and others showed that TNF-TNFR2 interaction was critical for the activation and expansion of functional CD4(+)  Foxp3(+) regulatory T (Treg) cells. We therefore examined the effect of PGRN on the proliferation of naturally occurring murine suppressive Treg cells induced by TNF. Consistent with our previous reports, TNF overcame the hyporesponsiveness of highly purified Treg cells to T-cell receptor stimulation. Furthermore, in the presence of interleukin-2, TNF preferentially stimulated proliferation of Treg cells contained in unfractionated CD4 cells. These effects of TNF on suppressive Treg cells were markedly increased by exogenous PGRN. TNF and TNFR2 interactions are required for this effect of PGRN, because the PGRN by itself did not stimulate Treg cell proliferation. The effect of PGRN on Treg cells was abrogated by antibody against TNFR2, and Treg cells deficient in TNFR2 also failed to respond to PGRN. Furthermore, PGRN also enhanced the proliferative responses of effector T cells to TNF, but to a lesser extent than that of Treg cells, presumably caused by the different levels of TNFR2 expression on these two subsets of CD4 cells. Hence, our data clearly show that PGRN promotes, rather than inhibits, the functional consequence of TNF-TNFR2 interaction on Treg cells.
authors.affiliation: Laboratory of Molecular Immunoregulation, Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA; School of Medicine, Yangtze University, Jingzhou, Hubei, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Hu
authors.forename: Haitao
authors.initials: H
authors.lastname: Xiao
authors.forename: Tingchen
authors.initials: T
authors.lastname: Shi
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oppenheim
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D000077155:Granulins; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077153:Progranulins; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D047889:Receptors, Tumor Necrosis Factor, Type II; D048069:Tumor Necrosis Factors
keywords: progranulin; proliferation; regulatory T cells; tumour necrosis factor; tumour necrosis factor receptor type 2