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

• Published in: Frontiers in Immunology
• Main Authors: QinLei Gu, Kenneth S. Tung, Ulrike M. Lorenz
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2023-03-01
• Subjects: SHP-1; tyrosine phosphatase; regulatory T cells; T cell signaling; inflammatory disease
• Online Access: https://www.frontiersin.org/articles/10.3389/fimmu.2023.1139326/full

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.