T cell-specific constitutive active SHP2 enhances T cell memory formation and reduces T cell activation

Abstract

Upon antigen recognition by the T cell receptor (TCR), a complex signaling network orchestrated by protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs) regulates the transmission of the extracellular signal to the nucleus. The role of the PTPs Src-homology 2 (SH2) domain-containing phosphatase 1 (SHP1, Ptpn6) and Src-homology 2 (SH2) domain-containing phosphatase 2 (SHP2, Ptpn11) have been studied in various cell types including T cells. Whereas SHP1 acts as an essential negative regulator of the proximal steps in T cell signalling, the role of SHP2 in T cell activation is still a matter of debate. Here, we analyzed the role of the constitutively active SHP2-D61Y-mutant in T cell activation using knock-in mice expressing the mutant form Ptpn11D61Y in T cells. We observed reduced numbers of CD8+ and increased numbers of CD4+ T cells in the bone marrow and spleen of young and aged SHP2-D61Y-mutant mice as well as in Influenza A Virus (IAV)-infected mice compared to controls. In addition, we found elevated frequencies of effector memory CD8+ T cells and an upregulation of the programmed cell death protein 1 (PD-1)-receptor on both CD4+ and CD8+ T cells. Functional analysis of SHP2-D61Y-mutated T cells revealed an induction of late apoptosis/necrosis, a reduced proliferation and altered signaling upon TCR stimulation. However, the ability of D61Y-mutant mice to clear viral infection was not affected. In conclusion, our data indicate an important regulatory role of SHP2 in T cell function, where the effect is determined by the kinetics of SHP2 phosphatase activity and differs in the presence of the permanently active and the temporally regulated phosphatase. Due to interaction of SHP2 with the PD-1-receptor targeting the protein-tyrosine phosphatase might be a valuable tool to enhance T cell activities in immunotherapy.

Intestinal microbiota analysis and network pharmacology reveal the mechanism by which Lianhua Qingwen capsule improves the immune function of mice infected with influenza A virus

“…Animal experiments have also confirmed that LHQW can reduce the viral load in the lungs of mice with viral pneumonia, reduce the expression of inflammatory factors in the lungs, and improve lung injury (Xia et al, 2020;Su et al, 2022). It is well known that viral clearance in the lung depends mainly on lymphocytes and macrophages (Bedi et al, 2022;Cammann et al, 2022;Harris and Borg, 2022;McGee et al, 2022;Verma et al, 2022;Wei et al, 2022;Zhang H. et al, 2022;Zhang M. et al, 2022); however, the present findings do not clarify how LHQW reduces the viral load in the lung and improves lung injury with viral pneumonia.…”

Overcoming Immune Checkpoint Therapy Resistance with SHP2 Inhibition in Cancer and Immune Cells: A Review of the Literature and Novel Combinatorial Approaches

“…PD-1 engagement with PD-L1 or PD-L2 triggers inhibitory signaling through its cytoplasmic domain, involving ITIM and ITSM motifs that recruit SHP2. The intricate interplay of SHP2 within the PD-1 pathway showcases its multifaceted influence on T-cell activation and immune response regulation, emphasizing its significance as a key mediator of immune checkpoint modulation [7,38,39].…”

“…SHP2 deficiency in T cells can lead to impaired TCR signaling and defective immune responses. The interplay of SHP2 with PD-1, including feedback mechanisms, and its broader impact on TCR signaling and immune regulation continue to be active areas of research, influencing our understanding of T-cell responses, especially in the context of cancer immunotherapy [3,39,41].…”