Requirement for CD28 co-stimulation is lower in SHP-1-deficient T cells.
This study provides biochemical and functional evidence pertaining to the role of the intracellular protein tyrosine phosphatase, SHP-1, in influencing thresholds for TCR activation. Although the loss of SHP-1 in thymocytes from motheaten mice had minimal effects on the initial rise of cytosolic Ca(2+) concentration following TCR triggering, the post-stimulation equilibrium levels of Ca(2+) were consistently elevated. In keeping with a SHP-1 effect on PLCgamma function, IP3 generation was increased in SHP-1 deficient thymocytes. Importantly, we demonstrate that loss of SHP-1 results in a relaxation of the normally stringent co-stimulatory requirements for IL-2 production. SHP-1 deficient single-positive CD4(+) thymocytes revealed a significantly enhanced capacity to produce IL-2 in response to anti-CD3 stimulation alone. In contrast, the simultaneous triggering of CD3 and CD28 was required for equivalent IL-2 production in control single-positive CD4(+) thymocytes. Furthermore, SHP-1 deficient thymocytes generated an increased and prolonged proliferative response to anti-CD3 stimulation alone. In addition, the simultaneous triggering of CD28 and CD3 resulted in equivalent proliferative responses in SHP-1-deficient and control thymocytes, suggesting that a strong co-stimulatory signal is able to override the effect of SHP-1 loss on TCR hyperresponsiveness. Collectively, these results suggest that SHP-1, rather than acting directly on TCR signaling, may indirectly raise thresholds for TCR triggering by modulating co-stimulatory signals.
Sathish
J G
JG
Department of Medicine, University of Wales College of Medicine, Cardiff, Wales, UK.
Johnson
K G
KG
LeRoy
F G
FG
Fuller
K J
KJ
Hallett
M B
MB
Brennan
P
P
Borysiewicz
L K
LK
Sims
M J
MJ
Matthews
R J
RJ
D000818:Animals; D018106:CD28 Antigens / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D010738:Type C Phospholipases / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
D018106:CD28 Antigens; D002118:Calcium; D002867:Chromones; D015544:Inositol 1,4,5-Trisphosphate; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D010738:Type C Phospholipases; D014443:Tyrosine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse