SHP-1 Regulates Antigen Cross-Presentation and Is Exploited by Leishmania to Evade Immunity

Khouili, Sofía C.; Cook, Emma C. L.; Hernández-García, Elena; Martínez-López, María; Conde-Garrosa, Ruth; Iborra, Salvador

doi:10.1016/j.celrep.2020.108468

Cited by 16 publications

(11 citation statements)

References 45 publications

(57 reference statements)

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“…Activation of PTPN6/SHP-1, in addition to regulating innate immunity, suppresses antigen cross-presentation (Ding et al, 2016), which some pathogens exploit to subvert adaptive immunity (C. Khouili et al, 2020). Further support for our finding of inter-individual variation in PTPN6/SHP-1 activity thus would have immediate implications both for understanding variations in pathogen susceptibility and for personalizing DC vaccines aimed at initiating CD8 T-cell responses.…”

Section: Discussionsupporting

confidence: 63%

CRISPR-based functional genomics in human dendritic cells

Jost

Jacobson

Hussmann

et al. 2021

eLife

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Dendritic cells (DCs) regulate processes ranging from antitumor and antiviral immunity to host-microbe communication at mucosal surfaces. It remains difficult, however, to genetically manipulate human DCs, limiting our ability to probe how DCs elicit specific immune responses. Here, we develop a CRISPR-Cas9 genome editing method for human monocyte-derived DCs (moDCs) that mediates knockouts with a median efficiency of >94% across >300 genes. Using this method, we perform genetic screens in moDCs, identifying mechanisms by which DCs tune responses to lipopolysaccharides from the human microbiome. In addition, we reveal donor-specific responses to lipopolysaccharides, underscoring the importance of assessing immune phenotypes in donor-derived cells, and identify candidate genes that control this specificity, highlighting the potential of our method to pinpoint determinants of inter-individual variation in immunity. Our work sets the stage for a systematic dissection of the immune signaling at the host-microbiome interface and for targeted engineering of DCs for neoantigen vaccination.

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Section: Discussionsupporting

confidence: 63%

CRISPR-based functional genomics in human dendritic cells

Jost

Jacobson

Hussmann

et al. 2021

eLife

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“…Third, in PTPN6/SHP-1 we identify a specific factor that contributes to this 283 variation, revealing how our approach enables dissecting the genetic bases of such inter-284 individual variation. Activation of PTPN6/SHP-1, in addition to regulating innate immunity, 285 suppresses antigen cross-presentation (Ding et al, 2016), which some pathogens exploit to 286 subvert adaptive immunity (C. Khouili et al, 2020). Our finding of inter-individual variation in 287 PTPN6/SHP-1 activity thus has immediate implications both for understanding variations in 288 14 pathogen susceptibility and for personalizing DC vaccines aimed at initiating CD8 T-cell responses.…”

Section: Discussionmentioning

confidence: 89%

CRISPR-based functional genomics in human dendritic cells

Jost

Jacobson

Hussmann

et al. 2020

Preprint

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Dendritic cells (DCs) regulate processes ranging from antitumor and antiviral immunity to host-microbe communication at mucosal surfaces. It remains difficult, however, to genetically manipulate human DCs, limiting our ability to probe how DCs elicit specific immune responses. Here, we develop a CRISPR/Cas9 genome editing method for human monocyte-derived DCs (moDCs) that mediates knockouts with a median efficiency of >93% across >300 genes. Using this method, we perform genetic screens in moDCs, identifying mechanisms by which DCs tune responses to lipopolysaccharides from the human microbiome. In addition, we reveal donor-specific responses to lipopolysaccharides, underscoring the importance of assessing immune phenotypes in donor-derived cells, and identify genes that control this specificity, highlighting the potential of our method to pinpoint determinants of inter-individual variation in immune responses. Our work sets the stage for a systematic dissection of the immune signaling at the host-microbiome interface and for targeted engineering of DCs for neoantigen vaccination.

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“…Intriguingly, PRM targeted analysis revealed that PTPN6 was significantly downregulated in PCP B cell exosomes. SHP-1 (PTPN6) exerts its regulatory role on T cells by inhibiting antigen-dependent activation and proliferation in Leishmania infection and other inflammatory conditions [ 49 , 50 ]. Moreover, in a tumor model of melanoma, knockdown of SHP-1 (PTPN6) expands antitumor T cell repertoire and dampens tumor growth, suggesting the potential application of SHP-1 (PTPN6) as immune checkpoint in future immune therapy [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Proteomic Profiling and Functional Analysis of B Cell-Derived Exosomes upon Pneumocystis Infection

Zhang

Rong

et al. 2022

Journal of Immunology Research

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Pneumocystis is a life-threatening fungal pathogen that frequently causes fatal pneumonia (PCP) in immunocompromised individuals. Recently, B cells have been reported to play a crucial role in the pathogenesis of PCP through producing antibodies and activating CD4+ T cell response. Exosomes are nanoscale small extracellular vesicles abundant with protein cargo and can mediate immune response during infectious disease. In this study, using tandem mass tag-based quantitative proteomics coupled with bioinformatic analysis, we attempted to characterize exosomes derived from B lymphocytes in response to PCP. Several proteins were verified by parallel reaction monitoring (PRM) analysis. Also, the effects of B cell exosomes on CD4+ T cell response and phagocytic function of macrophages were clarified. Briefly, 1701 proteins were identified from B cell exosomes, and the majority of them were reported in Vesiclepedia. A total of 51 differentially expressed proteins of B cell exosomes were found in response to PCP. They were mainly associated with immune response and transcription regulation. PRM analysis confirmed the significantly changed levels of histone H1.3, vimentin, and tyrosine-protein phosphatase nonreceptor type 6 (PTPN6). Moreover, a functional study revealed the proinflammatory profile of B cell exosomes on CD4+ T cell response in PCP. Taken together, our results suggest the involvement of exosomes derived from B cells in cell-to-cell communication, providing new information on the function of B cells in response to PCP.

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SHP-1 Regulates Antigen Cross-Presentation and Is Exploited by Leishmania to Evade Immunity

Cited by 16 publications

References 45 publications

CRISPR-based functional genomics in human dendritic cells

CRISPR-based functional genomics in human dendritic cells

CRISPR-based functional genomics in human dendritic cells

Proteomic Profiling and Functional Analysis of B Cell-Derived Exosomes upon Pneumocystis Infection

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