A prominent role for mucosal cystine/cysteine metabolism in intestinal immunoregulation.
OBJECTIVE
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.
Department of Surgery, Ruprecht-Karls-University, Heidelberg, Germany. brandl-sido@t-online.de
Bernd
B
Sido
Felix
F
Lasitschka
Thomas
T
Giese
Nikolaus
N
Gassler
Benjamin
B
Funke
Jutta
J
Schröder-Braunstein
Ulf
U
Brunnemer
Stefan C
SC
Meuer
Frank
F
Autschbach
D016022:Case-Control Studies; D018929:Cell Culture Techniques; D003545:Cysteine / Q000235:genetics / Q000378:metabolism*; D003553:Cystine / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D018928:Immunity, Mucosal / Q000502:physiology*; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology
D012333:RNA, Messenger; D003553:Cystine; D005978:Glutathione; D003545:Cysteine