Cargando…

CRISPR-Mediated Triple Knockout of SLAMF1, SLAMF5 and SLAMF6 Supports Positive Signaling Roles in NKT Cell Development

The SLAM family receptors contribute to diverse aspects of lymphocyte biology and signal via the small adaptor molecule SAP. Mutations affecting SAP lead to X-linked lymphoproliferative syndrome Type 1, a severe immunodysregulation characterized by fulminant mononucleosis, dysgammaglobulinemia, and...

Descripción completa

Detalles Bibliográficos
Autores principales: Huang, Bonnie, Gomez-Rodriguez, Julio, Preite, Silvia, Garrett, Lisa J., Harper, Ursula L., Schwartzberg, Pamela L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892526/
https://www.ncbi.nlm.nih.gov/pubmed/27258160
http://dx.doi.org/10.1371/journal.pone.0156072
_version_ 1782435404706742272
author Huang, Bonnie
Gomez-Rodriguez, Julio
Preite, Silvia
Garrett, Lisa J.
Harper, Ursula L.
Schwartzberg, Pamela L.
author_facet Huang, Bonnie
Gomez-Rodriguez, Julio
Preite, Silvia
Garrett, Lisa J.
Harper, Ursula L.
Schwartzberg, Pamela L.
author_sort Huang, Bonnie
collection PubMed
description The SLAM family receptors contribute to diverse aspects of lymphocyte biology and signal via the small adaptor molecule SAP. Mutations affecting SAP lead to X-linked lymphoproliferative syndrome Type 1, a severe immunodysregulation characterized by fulminant mononucleosis, dysgammaglobulinemia, and lymphoproliferation/lymphomas. Patients and mice having mutations affecting SAP also lack germinal centers due to a defect in T:B cell interactions and are devoid of invariant NKT (iNKT) cells. However, which and how SLAM family members contribute to these phenotypes remains uncertain. Three SLAM family members: SLAMF1, SLAMF5 and SLAMF6, are highly expressed on T follicular helper cells and germinal center B cells. SLAMF1 and SLAMF6 are also implicated in iNKT development. Although individual receptor knockout mice have limited iNKT and germinal center phenotypes compared to SAP knockout mice, the generation of multi-receptor knockout mice has been challenging, due to the genomic linkage of the genes encoding SLAM family members. Here, we used Cas9/CRISPR-based mutagenesis to generate mutations simultaneously in Slamf1, Slamf5 and Slamf6. Genetic disruption of all three receptors in triple-knockout mice (TKO) did not grossly affect conventional T or B cell development and led to mild defects in germinal center formation post-immunization. However, the TKO worsened defects in iNKT cells development seen in SLAMF6 single gene-targeted mice, supporting data on positive signaling and potential redundancy between these receptors.
format Online
Article
Text
id pubmed-4892526
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-48925262016-06-16 CRISPR-Mediated Triple Knockout of SLAMF1, SLAMF5 and SLAMF6 Supports Positive Signaling Roles in NKT Cell Development Huang, Bonnie Gomez-Rodriguez, Julio Preite, Silvia Garrett, Lisa J. Harper, Ursula L. Schwartzberg, Pamela L. PLoS One Research Article The SLAM family receptors contribute to diverse aspects of lymphocyte biology and signal via the small adaptor molecule SAP. Mutations affecting SAP lead to X-linked lymphoproliferative syndrome Type 1, a severe immunodysregulation characterized by fulminant mononucleosis, dysgammaglobulinemia, and lymphoproliferation/lymphomas. Patients and mice having mutations affecting SAP also lack germinal centers due to a defect in T:B cell interactions and are devoid of invariant NKT (iNKT) cells. However, which and how SLAM family members contribute to these phenotypes remains uncertain. Three SLAM family members: SLAMF1, SLAMF5 and SLAMF6, are highly expressed on T follicular helper cells and germinal center B cells. SLAMF1 and SLAMF6 are also implicated in iNKT development. Although individual receptor knockout mice have limited iNKT and germinal center phenotypes compared to SAP knockout mice, the generation of multi-receptor knockout mice has been challenging, due to the genomic linkage of the genes encoding SLAM family members. Here, we used Cas9/CRISPR-based mutagenesis to generate mutations simultaneously in Slamf1, Slamf5 and Slamf6. Genetic disruption of all three receptors in triple-knockout mice (TKO) did not grossly affect conventional T or B cell development and led to mild defects in germinal center formation post-immunization. However, the TKO worsened defects in iNKT cells development seen in SLAMF6 single gene-targeted mice, supporting data on positive signaling and potential redundancy between these receptors. Public Library of Science 2016-06-03 /pmc/articles/PMC4892526/ /pubmed/27258160 http://dx.doi.org/10.1371/journal.pone.0156072 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Huang, Bonnie
Gomez-Rodriguez, Julio
Preite, Silvia
Garrett, Lisa J.
Harper, Ursula L.
Schwartzberg, Pamela L.
CRISPR-Mediated Triple Knockout of SLAMF1, SLAMF5 and SLAMF6 Supports Positive Signaling Roles in NKT Cell Development
title CRISPR-Mediated Triple Knockout of SLAMF1, SLAMF5 and SLAMF6 Supports Positive Signaling Roles in NKT Cell Development
title_full CRISPR-Mediated Triple Knockout of SLAMF1, SLAMF5 and SLAMF6 Supports Positive Signaling Roles in NKT Cell Development
title_fullStr CRISPR-Mediated Triple Knockout of SLAMF1, SLAMF5 and SLAMF6 Supports Positive Signaling Roles in NKT Cell Development
title_full_unstemmed CRISPR-Mediated Triple Knockout of SLAMF1, SLAMF5 and SLAMF6 Supports Positive Signaling Roles in NKT Cell Development
title_short CRISPR-Mediated Triple Knockout of SLAMF1, SLAMF5 and SLAMF6 Supports Positive Signaling Roles in NKT Cell Development
title_sort crispr-mediated triple knockout of slamf1, slamf5 and slamf6 supports positive signaling roles in nkt cell development
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892526/
https://www.ncbi.nlm.nih.gov/pubmed/27258160
http://dx.doi.org/10.1371/journal.pone.0156072
work_keys_str_mv AT huangbonnie crisprmediatedtripleknockoutofslamf1slamf5andslamf6supportspositivesignalingrolesinnktcelldevelopment
AT gomezrodriguezjulio crisprmediatedtripleknockoutofslamf1slamf5andslamf6supportspositivesignalingrolesinnktcelldevelopment
AT preitesilvia crisprmediatedtripleknockoutofslamf1slamf5andslamf6supportspositivesignalingrolesinnktcelldevelopment
AT garrettlisaj crisprmediatedtripleknockoutofslamf1slamf5andslamf6supportspositivesignalingrolesinnktcelldevelopment
AT harperursulal crisprmediatedtripleknockoutofslamf1slamf5andslamf6supportspositivesignalingrolesinnktcelldevelopment
AT schwartzbergpamelal crisprmediatedtripleknockoutofslamf1slamf5andslamf6supportspositivesignalingrolesinnktcelldevelopment