BACKGROUND & AIMS: T-cell receptor reactivity of intestinal lamina propria T cells (LP-T) critically depends on the capacity of local accessory cells to secrete cysteine. For T cells, cysteine is the limiting precursor for glutathione synthesis, a prerequisite for antigen-dependent proliferation. We aimed to determine the role of the redoxactive microenvironment for hyporeactivity of LP-T in normal human gut vs hyperreactivity of LP-T in inflammatory bowel disease. METHODS: Parameters relevant to cysteine production, determined as acid-soluble thiol, by intestinal lamina propria macrophages (LP-MO) vs peripheral blood monocytes were investigated (L-[(35)S]cystine uptake via system x(c)(-), messenger RNA, and protein expression of the cystine transporter subunit xCT). Glutathione levels in LP-T and peripheral blood T cells were analyzed both spectrophotometrically and by immunofluorescent staining in situ and in vitro. RESULTS: LP-MO from normal gut, unlike peripheral blood monocytes, are unable to take up cystine, which is due to a deficient expression of the transporter xCT in situ and in vitro. As a consequence, LP-MO do not secrete cysteine. The glutathione content in LP-T from normal gut is <50% of that in autologous peripheral blood T cells. In contrast, in inflammatory bowel disease, CD14(+)CD68(+) LP-MO express xCT and secrete substantial amounts of cysteine upon stimulation, which results in high glutathione levels and full T-cell receptor reactivity in LP-T. CONCLUSIONS: The antioxidative microenvironment of LP-T in inflammatory bowel disease and the prooxidative microenvironment in normal gut explain the differential T-cell receptor reactivities.
BACKGROUND & AIMS: T-cell receptor reactivity of intestinal lamina propria T cells (LP-T) critically depends on the capacity of local accessory cells to secrete cysteine. For T cells, cysteine is the limiting precursor for glutathione synthesis, a prerequisite for antigen-dependent proliferation. We aimed to determine the role of the redoxactive microenvironment for hyporeactivity of LP-T in normal human gut vs hyperreactivity of LP-T in inflammatory bowel disease. METHODS: Parameters relevant to cysteine production, determined as acid-soluble thiol, by intestinal lamina propria macrophages (LP-MO) vs peripheral blood monocytes were investigated (L-[(35)S]cystine uptake via system x(c)(-), messenger RNA, and protein expression of the cystine transporter subunit xCT). Glutathione levels in LP-T and peripheral blood T cells were analyzed both spectrophotometrically and by immunofluorescent staining in situ and in vitro. RESULTS: LP-MO from normal gut, unlike peripheral blood monocytes, are unable to take up cystine, which is due to a deficient expression of the transporter xCT in situ and in vitro. As a consequence, LP-MO do not secrete cysteine. The glutathione content in LP-T from normal gut is <50% of that in autologous peripheral blood T cells. In contrast, in inflammatory bowel disease, CD14(+)CD68(+) LP-MO express xCT and secrete substantial amounts of cysteine upon stimulation, which results in high glutathione levels and full T-cell receptor reactivity in LP-T. CONCLUSIONS: The antioxidative microenvironment of LP-T in inflammatory bowel disease and the prooxidative microenvironment in normal gut explain the differential T-cell receptor reactivities.
Authors: Jan Lewerenz; Sandra J Hewett; Ying Huang; Maria Lambros; Peter W Gout; Peter W Kalivas; Ann Massie; Ilse Smolders; Axel Methner; Mathias Pergande; Sylvia B Smith; Vadivel Ganapathy; Pamela Maher Journal: Antioxid Redox Signal Date: 2012-08-03 Impact factor: 8.401
Authors: Alessandro Prestipino; Alica J Emhardt; Konrad Aumann; David O'Sullivan; Sivahari P Gorantla; Sandra Duquesne; Wolfgang Melchinger; Lukas Braun; Slavica Vuckovic; Melanie Boerries; Hauke Busch; Sebastian Halbach; Sandra Pennisi; Teresa Poggio; Petya Apostolova; Pia Veratti; Michael Hettich; Gabriele Niedermann; Mark Bartholomä; Khalid Shoumariyeh; Jonas S Jutzi; Julius Wehrle; Christine Dierks; Heiko Becker; Annette Schmitt-Graeff; Marie Follo; Dietmar Pfeifer; Jan Rohr; Sebastian Fuchs; Stephan Ehl; Frederike A Hartl; Susana Minguet; Cornelius Miething; Florian H Heidel; Nicolaus Kröger; Ioanna Triviai; Tilman Brummer; Jürgen Finke; Anna L Illert; Eliana Ruggiero; Chiara Bonini; Justus Duyster; Heike L Pahl; Steven W Lane; Geoffrey R Hill; Bruce R Blazar; Nikolas von Bubnoff; Erika L Pearce; Robert Zeiser Journal: Sci Transl Med Date: 2018-02-21 Impact factor: 17.956
Authors: Marleen T J van Ampting; Arjan J Schonewille; Carolien Vink; Robert Jan M Brummer; Roelof van der Meer; Ingeborg M J Bovee-Oudenhoven Journal: BMC Physiol Date: 2009-04-17