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

Gu, QinLei, Microbiology - School of Medicine, University of Virginia
Lorenz, Ulrike, University of Virginia

In the immune system, regulatory T cells (Treg cells) are one of the crucial players contributing to the maintenance of immunological tolerance and homeostasis. A delicate balance is achieved between the activation of conventional T cells (Tcon cells) and the suppression by Treg cells to support a healthy and functional immune system. Previous studies demonstrated that the tyrosine phosphatase SHP-1, a negative regulator of TCR signaling, modulates Tcon cell resistance to Treg-mediated suppression, thereby shaping this activation-suppression balance. However, the role of SHP-1 in Treg cells is still not fully understood.
In this work, we revealed how SHP-1 affects the functional phenotype of Treg cells and modulates Treg suppressive function. At the intracellular signaling level, SHP-1 attenuates Treg Akt phosphorylation, and loss of SHP-1 drives Treg cells towards a glycolysis pathway. At the functional Treg cell level, SHP-1 limits the in vivo accumulation of CD44hiCD62Llo T cells with the CD8+ and CD4+ Tcon cell populations under steady state condition. Interestingly under challenge, SHP-1-deficient Treg cells are less efficient in suppressing inflammation in vivo, once transferred, they may not survive or migrate to peripheral inflammation sites.
In addition, this study investigates the role of SHP-1 in Treg cells in aged mice. Incidental observations suggest that FOXP3+ Treg cell specific SHP-1 deficient mice may develop splenomegaly. Instead, preliminary results suggest a trend of FOXP3+ Treg loss and down regulation of ICOS expression in the aged mice.
Overall, this work identifies SHP-1 as a critical player in mediating the balance between T cell activation and suppression. Therefore, SHP-1 could potentially become a promising therapeutic target for fine-tuning the balance between Treg-mediated suppression and Tcon activation/resistance to suppression.

PHD (Doctor of Philosophy)
Treg, SHP-1, Tcon
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