A prominent role for mucosal cystine/cysteine metabolism in intestinal immunoregulation

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...

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Hauptverfasser: Sido, Bernd (VerfasserIn) , Lasitschka, Felix (VerfasserIn) , Giese, Thomas (VerfasserIn) , Gaßler, Nikolaus (VerfasserIn) , Funke, Benjamin (VerfasserIn) , Schröder-Braunstein, Jutta (VerfasserIn) , Brunnemer, Ulf (VerfasserIn) , Meuer, Stefan (VerfasserIn) , Autschbach, Frank (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2008
In: Gastroenterology
Year: 2008, Jahrgang: 134, Heft: 1, Pages: 179-191
ISSN:1528-0012
DOI:10.1053/j.gastro.2007.11.001
Online-Zugang:Verlag, lizenzpflichtig, Volltext: http://dx.doi.org/10.1053/j.gastro.2007.11.001
Verlag, lizenzpflichtig, Volltext: https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(07)01991-9
Volltext
Verfasserangaben:Bernd Sido, Felix Lasitschka, Thomas Giese, Nikolaus Gassler, Benjamin Funke, Jutta Schröder-Braunstein, Ulf Brunnemer, Stefan C. Meuer, and Frank Autschbach

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520 |a 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. 
650 4 |a Case-Control Studies 
650 4 |a Cell Culture Techniques 
650 4 |a Cysteine 
650 4 |a Cystine 
650 4 |a Glutathione 
650 4 |a Humans 
650 4 |a Immunity, Mucosal 
650 4 |a Inflammatory Bowel Diseases 
650 4 |a Intestinal Mucosa 
650 4 |a RNA, Messenger 
650 4 |a T-Lymphocytes 
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