TY - JOUR
T1 - T cells deficient in the tyrosine phosphatase SHP-1 resist suppression by regulatory T cells
AU - Mercadante, Emily R.
AU - Lorenz, Ulrike M.
N1 - Funding Information:
This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant 1F31AI110146 (to E.R.M.), National Institute of General Medical Sciences Grant 5R01GM064709 (to U.M.L.), and by National Heart, Lung, and Blood Institute Grant 1P01HL120840 (to U.M.L.).
Publisher Copyright:
Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved.
PY - 2017/7/1
Y1 - 2017/7/1
N2 - The balance between activation of T cells and their suppression by regulatory T cells (Tregs) is dysregulated in autoimmune diseases and cancer. Autoimmune diseases feature T cells that are resistant to suppression by Tregs, whereas in cancer, T cells are unable to mount antitumor responses due to the Treg-enriched suppressive microenvironment. In this study, we observed that loss of the tyrosine phosphatase SHP-1, a negative regulator of TCR signaling, renders naive CD4+ and CD8+ T cells resistant to Tregmediated suppression in a T cell-intrinsic manner. At the intracellular level, SHP-1 controlled the extent of Akt activation, which has been linked to the induction of T cell resistance to Treg suppression. Finally, under conditions of homeostatic expansion, SHP-1-deficient CD4+ T cells resisted Treg suppression in vivo. Collectively, these data establish SHP-1 as a critical player in setting the threshold downstream of TCR signaling and identify a novel function of SHP-1 as a regulator of T cell susceptibility to Treg-mediated suppression in vitro and in vivo. Thus, SHP-1 could represent a potential novel immunotherapeutic target to modulate susceptibility of T cells to Treg suppression.
AB - The balance between activation of T cells and their suppression by regulatory T cells (Tregs) is dysregulated in autoimmune diseases and cancer. Autoimmune diseases feature T cells that are resistant to suppression by Tregs, whereas in cancer, T cells are unable to mount antitumor responses due to the Treg-enriched suppressive microenvironment. In this study, we observed that loss of the tyrosine phosphatase SHP-1, a negative regulator of TCR signaling, renders naive CD4+ and CD8+ T cells resistant to Tregmediated suppression in a T cell-intrinsic manner. At the intracellular level, SHP-1 controlled the extent of Akt activation, which has been linked to the induction of T cell resistance to Treg suppression. Finally, under conditions of homeostatic expansion, SHP-1-deficient CD4+ T cells resisted Treg suppression in vivo. Collectively, these data establish SHP-1 as a critical player in setting the threshold downstream of TCR signaling and identify a novel function of SHP-1 as a regulator of T cell susceptibility to Treg-mediated suppression in vitro and in vivo. Thus, SHP-1 could represent a potential novel immunotherapeutic target to modulate susceptibility of T cells to Treg suppression.
UR - http://www.scopus.com/inward/record.url?scp=85021123674&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1602171
DO - 10.4049/jimmunol.1602171
M3 - Article
C2 - 28550200
AN - SCOPUS:85021123674
SN - 0022-1767
VL - 199
SP - 129
EP - 137
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -