Shp-2 Is Dispensable for Establishing T Cell Exhaustion and for PD-1 Signaling In Vivo

Giorgia Rota, Charlène Niogret, Anh Thu Dang, Cristina Ramon Barros, Nicolas Pierre Fonta, Francesca Alfei, Leonor Morgado, Dietmar Zehn, Walter Birchmeier, Eric Vivier, Greta Guarda

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

111 Zitate (Scopus)

Abstract

In chronic infection and cancer, T cells acquire a dysfunctional state characterized by the expression of inhibitory receptors. In vitro studies implicated the phosphatase Shp-2 downstream of these receptors, including PD-1. However, whether Shp-2 is responsible in vivo for such dysfunctional responses remains elusive. To address this, we generated T cell-specific Shp-2-deficient mice. These mice did not show differences in controlling chronic viral infections. In this context, Shp-2-deleted CD8 + T lymphocytes expanded moderately better but were less polyfunctional than control cells. Mice with Shp-2-deficient T cells also showed no significant improvement in controlling immunogenic tumors and responded similarly to controls to α-PD-1 treatment. We therefore showed that Shp-2 is dispensable in T cells for globally establishing exhaustion and for PD-1 signaling in vivo. These results reveal the existence of redundant mechanisms downstream of inhibitory receptors and represent the foundation for defining these relevant molecular events. In vitro data indicate that Shp-2 is engaged by PD-1 and contributes to T cell exhaustion. Rota et al. show that Shp-2-deficient T cells acquire a dysfunctional state when exposed to chronic antigen in vivo and respond to PD-1 blockade, indicating the existence of additional signaling factors.

OriginalspracheEnglisch
Seiten (von - bis)39-49
Seitenumfang11
FachzeitschriftCell Reports
Jahrgang23
Ausgabenummer1
DOIs
PublikationsstatusVeröffentlicht - 3 Apr. 2018

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