Redox equilibrium in mucosal T cells tunes the intestinal TCR signaling threshold.
Mucosal immune tolerance in the healthy intestine is typified by lamina propria T cell (LPT) functional hyporesponsiveness after TCR engagement when compared with peripheral blood T cell (PBT). When LPT from an inflamed intestine are activated through TCR cross-linking, their responsiveness is stronger. LPT are thus capable of switching from a tolerant to a reactive state, toggling between high and low thresholds of activation. We demonstrate that in normal LPT global tyrosine phosphorylation upon TCR cross-linking or an increase in intracellular H2O2, an inhibitor of protein tyrosine phosphatases, is muted. Thus, we propose that LPT have a greater reducing capacity than PBT, shifting the balance between kinases and protein tyrosine phosphatases in favor of the latter. Surface gamma-glutamyl transpeptidase, an indirect indicator of redox potential, and glutathione are significantly elevated in LPT compared with PBT, suggesting that elevated glutathione detoxifies TCR-induced reactive oxygen species. When glutathione is depleted, TCR-induced LPT tyrosine phosphorylation rises to PBT levels. Conversely, increasing glutathione in PBT attenuates tyrosine phosphorylation. In LPT isolated from inflamed mucosa, TCR cross-linking induces greater phosphorylation, and gamma-glutamyl transpeptidase levels are reduced compared with those from autologous noninflamed tissue. We conclude that the high TCR signaling threshold of mucosal T cells is tuned by intracellular redox equilibrium, whose dysregulation may mediate intestinal inflammation.
Reyes
Brenda M Rivera
BM
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Danese
Silvio
S
Sans
Miquel
M
Fiocchi
Claudio
C
Levine
Alan D
AD
D002478:Cells, Cultured; D005978:Glutathione / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007108:Immune Tolerance; D007156:Immunologic Memory; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D007424:Intracellular Fluid / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects; D010084:Oxidation-Reduction; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D017382:Reactive Oxygen Species; D011948:Receptors, Antigen, T-Cell; D006861:Hydrogen Peroxide; D005723:gamma-Glutamyltransferase; D017027:Protein Tyrosine Phosphatases; D005978:Glutathione