TY - JOUR
T1 - Treg-specific deletion of the phosphatase SHP-1 impairs control of inflammation in vivo
AU - Gu, Qin Lei
AU - Tung, Kenneth S.
AU - Lorenz, Ulrike M.
N1 - Publisher Copyright:
Copyright © 2023 Gu, Tung and Lorenz.
PY - 2023
Y1 - 2023
N2 - Introduction: To 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. Methods: We 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. Results: We 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. Conclusion: Our data identify SHP-1 as an important intracellular mediator for fine-tuning the balance between Treg-mediated suppression and Tcon activation/resistance.
AB - Introduction: To 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. Methods: We 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. Results: We 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. Conclusion: Our data identify SHP-1 as an important intracellular mediator for fine-tuning the balance between Treg-mediated suppression and Tcon activation/resistance.
KW - SHP-1
KW - T cell signaling
KW - inflammatory disease
KW - regulatory T cells
KW - tyrosine phosphatase
UR - http://www.scopus.com/inward/record.url?scp=85151352782&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2023.1139326
DO - 10.3389/fimmu.2023.1139326
M3 - Article
C2 - 37006301
AN - SCOPUS:85151352782
SN - 1664-3224
VL - 14
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 1139326
ER -