Treg-specific deletion of the phosphatase SHP-1 impairs control of inflammation in vivo

Abstract

IntroductionTo achieve a healthy and functional immune system, a delicate balance exists between the activation of conventional T cells (Tcon cells) and the suppression by regulatory T cells (Treg). The tyrosine phosphatase SHP-1, a negative regulator of TCR signaling, shapes this ‘activation-suppression’ balance by modulating Tcon cell resistance to Treg-mediated suppression. Treg cells also express SHP-1, but its role in influencing Treg function is still not fully understood. MethodsWe generated a Treg-specific SHP-1 deletion model, Foxp3Cre+ Shp-1f/f, to address how SHP-1 affects Treg function and thereby contributes to T cell homeostasis using a combination of ex vivo studies and in vivo models of inflammation and autoimmunity.ResultsWe show that SHP-1 modulates Treg suppressive function at different levels. First, at the intracellular signaling level in Treg cells, SHP-1 attenuates TCR-dependent Akt phosphorylation, with loss of SHP-1 driving Treg cells towards a glycolysis pathway. At the functional level, SHP-1 expression limits the in vivo accumulation of CD44hiCD62Llo T cells within the steady state Tcon populations (both CD8+ as well as CD4+ Tcon). Further, SHP-1-deficient Treg cells are less efficient in suppressing inflammation in vivo; mechanistically, this appears to be due to a failure to survive or a defect in migration of SHP-1-deficient Treg cells to peripheral inflammation sites.ConclusionOur data identify SHP-1 as an important intracellular mediator for fine-tuning the balance between Treg-mediated suppression and Tcon activation/resistance.

SHP-1 interacts with NFκB1 to inhibit its phosphorylation and nuclear translocation to suppress excessive bacterial inflammation

“…The results were intriguing, which may explain why SHP-1 showed differential expression after the same bacterial infection in the same teleost in our previous study (36), i.e., SHP-1 underwent dynamic regulation to maintain the cell and tissue homeostasis to avoid death after infection. These results are consistent with its effects in mammals, whereby SHP-1 attenuates corneal damage induced by LPS challenge (37) as well as reduces lymphocyte infiltration and epithelia hyperplasia/metaplasia in mouse stomach (38).…”

The implication of targeting PD-1:PD-L1 pathway in treating sepsis through immunostimulatory and anti-inflammatory pathways

“…Additionally, PD-L1 plays a key role in regulating the suppression of iALI by Treg cells, which may be related to the activation of SHP-1 of lung tissue ( 133 , 134 ). The activation of SHP-1 is associated with the loss of the protective effect of Tregs in vivo ( 135 ). Equally important, PD-L1 binds to the p85 subunit of PI3K on the endoplasmic reticulum (ER) of neutrophils, inhibiting autophagy through the PI3K/Akt/mTOR pathway and promoting the release of neutrophil extracellular traps (NETs) ( 136 ).…”