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Robert John Barry, David Withers, Graham R Wallace, Peter Lane, Philip Ian Murray, John Curnow; The TGFβ co-receptor betaglycan (TGFBR3) is not implicated in TGFβ-dependent T-cell responses. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):849.
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© ARVO (1962-2015); The Authors (2016-present)
Transforming Growth Factor-β (TGFβ) is considered an important immunoregulatory cytokine. In experimental models of uveitis, TGFβ, in the presence of pro-inflammatory co-stimulatory molecules, drives differentiation of naïve CD4+ T-cells to a pathogenic Th17 phenotype. TGFβ exists in three isoforms and signals through a receptor comprising three subunits. The role of TGFBR1 and 2 is well characterized but the function of TGFBR3 (betaglycan) is unclear. Betaglycan is implicated in embryogenesis, carcinogenesis, and intrathymic T-cell development, but its role in peripheral immune responses is unknown. Betgalycan is considered necessary to present TGFβ2, but not the other isoforms, to the TGFBR1/2 receptor complex and may be important in environments where TGFβ2 predominates, such as the eye. Our aim was to examine the role of betaglycan in controlling T-cell responses to TGFβ.
Homozygous betaglycan deficiency is embryonic lethal; we therefore generated fetal liver chimeras in rag-deficient mice to create a model in which all T and B-cells lack betaglycan. We phenotyped this model, performed controlled antigenic challenge in vivo to assess Th1, Treg and Th17 responses, and created naive T-cell differentiation assays in vitro to assess FoxP3 induction by all isoforms of TGFβ.
Betaglycan-deficient mice showed reconstitution of peripheral lymphocyte populations within 6 weeks of cell transfer. We observed sporadic immune activation in betaglycan-deficient mice, demonstrated by increased proportions of effector CD4+ and CD8+ T-cells in circulating, lymph node and splenocyte populations. We have found no evidence of circulating serum autoantibodies. No significant difference was observed between betaglycan-deficient and wild-type chimeras in response to antigenic challenge by attenuated Listeria monocytogenes, incomplete Freund's adjuvant or bacterial porins. All isoforms of TGFβ induced FoxP3 expression in naïve CD4+ T-cells with no significant difference between cells derived from betaglycan-deficient and wild-type chimeras.
We have created a novel experimental model in which to assess the role of betaglycan on mature T-cell responses. In contrast to its role in other areas, betaglycan appears unnecessary for TGFβ-dependent T-cell responses in our assays. Further work is required to assess betaglycan function in environments where TGFβ2-driven T-cell responses predominate.
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