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PD-L2 suppresses T cell signaling via coinhibitory microcluster formation and SHP2 phosphatase recruitment.

ABSTRACT: The coinhibitory receptor, PD-1, is of major importance for the suppression of T cell activation in various types of immune responses. A high-resolution imaging study showed that PD-1 forms a coinhibitory signalosome, "PD-1 microcluster", with the phosphatase, SHP2, to dephosphorylate the TCR/CD3 complex and its downstream signaling molecules. Such a consecutive reaction entirely depended on PD-1-PD-L1/2 binding. PD-L2 is expressed on professional antigen-presenting cells and also on some tumor cells, which possibly explains the discrepant efficacy of immune checkpoint therapy for PD-L1-negative tumors. Here, we performed precise imaging analysis of PD-L2 forming PD-1-PD-L2 clusters associating with SHP2. PD-L2 could compete with PD-L1 for binding to PD-1, occupying the same space at TCR microclusters. The PD-1 microcluster formation was inhibited by certain mAbs with functional consequences. Thus, PD-1 microcluster formation provides a visible index for the effectiveness of anti-PD-1- or anti-PD-L1/2-mediated T cell suppression. PD-L2 may exert immune suppressive responses cooperatively with PD-L1 on the microcluster scale.

SUBMITTER: Takehara T

PROVIDER: S-EPMC8121797 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Influenza A virus (IAV) is a highly contagious pathogen, causing acute respiratory illnesses in human beings and animals and frequently giving rise to epidemic outbreaks. Evasion by IAV of host immunity facilitates viral replication and spread, which can be initiated through various mechanisms, including epidermal growth factor receptor (EGFR) activation. However, how EGFR mediates the suppression of antiviral systems remains unclear. Here, we examined host innate immune responses and their relevant signaling to EGFR upon IAV infection. IAV was found to induce the phosphorylation of EGFR and extracellular signal-regulated kinase (ERK) at an early stage of infection. Inhibition of EGFR or ERK suppressed the viral replication but increased the expression of type I and type III interferons (IFNs) and interferon-stimulated genes (ISGs), supporting the idea that IAV escapes from antiviral innate immunity by activating EGFR/ERK signaling. Meanwhile, IAV infection also induced the activation of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2). Pharmacological inhibition or small interfering RNA (siRNA)-based silencing of SHP2 enhanced the IFN-dependent antiviral activity and reduced virion production. Furthermore, knockdown of SHP2 attenuated the EGFR-mediated ERK phosphorylation triggered by viral infection or EGF stimulation. Conversely, ectopic expression of constitutively active SHP2 noticeably promoted ERK activation and viral replication, concomitant with diminished immune function. Altogether, the results indicate that SHP2 is crucial for IAV-induced activation of the EGFR/ERK pathway to suppress host antiviral responses.IMPORTANCE Viral immune evasion is the most important strategy whereby viruses evolve for their survival. This work shows that influenza A virus (IAV) suppressed the antiviral innate immunity through downregulation of IFNs and ISGs by activating EGFR/ERK signaling. Meanwhile, IAV also induced the activation of protein tyrosine phosphatase SHP2, which was found to be responsible for modulating the EGFR-mediated ERK activity and subsequent antiviral effectiveness both in vitro and in vivo The results suggest that SHP2 is a key signal transducer between EGFR and ERK and plays a crucial role in suppressing host innate immunity during IAV infection. The finding enhances our understanding of influenza immune evasion and provides a new therapeutic approach to viral infection.

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PD-L2 suppresses T cell signaling via coinhibitory microcluster formation and SHP2 phosphatase recruitment.

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