IL-10 inhibits CD28 and ICOS costimulations of T cells via src homology 2 domain-containing protein tyrosine phosphatase 1.
BACKGROUND
Specific T-cell activation requires T-cell receptor stimulation and the generation of costimulatory signals. Major costimulatory signals are delivered to T cells by the interaction of CD28 and inducible costimulator (ICOS).


OBJECTIVE
To investigate the molecular pathways involved in direct T-cell suppression by IL-10.


METHODS
T-cell proliferation analysis, immunoprecipitations, and Western blots were performed after T-cell receptor and CD28 and ICOS stimulations in the absence or presence of IL-10. Dominant-negative src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) overexpression, small inhibitory RNA, and SHP-1-deficient and IL-10-deficient mice were used.


RESULTS
IL-10 receptor-associated tyrosine kinase Tyk-2 acts as a constitutive reservoir for SHP-1 in resting T cells, and then tyrosine phosphorylates SHP-1 on IL-10 binding. SHP-1 rapidly binds to CD28 and ICOS costimulatory receptors and dephosphorylates them within minutes. In consequence, the binding of phosphatidylinositol 3-kinase to either costimulatory receptor no longer occurs, and downstream signaling is inhibited. Accordingly, spleen cells from SHP-1-deficient mice showed increased proliferation with CD28 and ICOS stimulation in comparison with wild-type mice, which was not suppressed by IL-10. Generation of dominant-negative SHP-1-overexpressing T cells or silencing of the SHP-1 gene by small inhibitory RNA both altered SHP-1 functions and abolished the T-cell suppressive effect of IL-10.


CONCLUSIONS
The rapid inhibition of the CD28 or ICOS costimulatory pathways by SHP-1 represents a novel mechanism for direct T-cell suppression by IL-10.


CONCLUSIONS
Molecular mechanisms of direct T-cell suppression by IL-10 may provide a novel target for therapy of allergy/asthma and autoimmune disease.
Taylor
Alison
A
Swiss Institute of Allergy and Asthma Research, Davos, Switzerland.
Akdis
Mübeccel
M
Joss
Andrea
A
Akkoç
Tunç
T
Wenig
Renate
R
Colonna
Marco
M
Daigle
Isabelle
I
Flory
Egbert
E
Blaser
Kurt
K
Akdis
Cezmi A
CA
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D018106:CD28 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*
D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; C556692:ICOS protein, human; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10; D019869:Phosphatidylinositol 3-Kinases; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6