Cargando…

Proteomic analysis in primary T cells reveals IL-7 alters T cell receptor thresholding via CYTIP/cytohesin/LFA-1 localisation and activation

The ability of the cellular immune system to discriminate self from foreign antigens depends on the appropriate calibration of the T cell receptor (TCR) signalling threshold. The lymphocyte homeostatic cytokine interleukin 7 (IL-7) is known to affect TCR thresholding, but the molecular mechanism is...

Descripción completa

Detalles Bibliográficos
Autores principales: Queiroz, Rayner M. L., Piper, Siân C., Rees, Johanna S., Strickson, Sam, Briend, Emmanuel, Low, Choon Pei, Ferguson, G. John, Lilley, Kathryn S., Jackson, Antony P., Finch, Donna K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8883493/
https://www.ncbi.nlm.nih.gov/pubmed/35015072
http://dx.doi.org/10.1042/BCJ20210313
_version_ 1784659939965272064
author Queiroz, Rayner M. L.
Piper, Siân C.
Rees, Johanna S.
Strickson, Sam
Briend, Emmanuel
Low, Choon Pei
Ferguson, G. John
Lilley, Kathryn S.
Jackson, Antony P.
Finch, Donna K.
author_facet Queiroz, Rayner M. L.
Piper, Siân C.
Rees, Johanna S.
Strickson, Sam
Briend, Emmanuel
Low, Choon Pei
Ferguson, G. John
Lilley, Kathryn S.
Jackson, Antony P.
Finch, Donna K.
author_sort Queiroz, Rayner M. L.
collection PubMed
description The ability of the cellular immune system to discriminate self from foreign antigens depends on the appropriate calibration of the T cell receptor (TCR) signalling threshold. The lymphocyte homeostatic cytokine interleukin 7 (IL-7) is known to affect TCR thresholding, but the molecular mechanism is not fully elucidated. A better understanding of this process is highly relevant in the context of autoimmune disease therapy and cancer immunotherapy. We sought to characterise the early signalling events attributable to IL-7 priming; in particular, the altered phosphorylation of signal transduction proteins and their molecular localisation to the TCR. By integrating high-resolution proximity- phospho-proteomic and imaging approaches using primary T cells, rather than engineered cell lines or an in vitro expanded T cell population, we uncovered transduction events previously not linked to IL-7. We show that IL-7 leads to dephosphorylation of cytohesin interacting protein (CYTIP) at a hitherto undescribed phosphorylation site (pThr280) and alters the co-localisation of cytohesin-1 with the TCR and LFA-1 integrin. These results show that IL-7, acting via CYTIP and cytohesin-1, may impact TCR activation thresholds by enhancing the co-clustering of TCR and LFA-1 integrin.
format Online
Article
Text
id pubmed-8883493
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Portland Press Ltd.
record_format MEDLINE/PubMed
spelling pubmed-88834932022-03-10 Proteomic analysis in primary T cells reveals IL-7 alters T cell receptor thresholding via CYTIP/cytohesin/LFA-1 localisation and activation Queiroz, Rayner M. L. Piper, Siân C. Rees, Johanna S. Strickson, Sam Briend, Emmanuel Low, Choon Pei Ferguson, G. John Lilley, Kathryn S. Jackson, Antony P. Finch, Donna K. Biochem J Immunology & Inflammation The ability of the cellular immune system to discriminate self from foreign antigens depends on the appropriate calibration of the T cell receptor (TCR) signalling threshold. The lymphocyte homeostatic cytokine interleukin 7 (IL-7) is known to affect TCR thresholding, but the molecular mechanism is not fully elucidated. A better understanding of this process is highly relevant in the context of autoimmune disease therapy and cancer immunotherapy. We sought to characterise the early signalling events attributable to IL-7 priming; in particular, the altered phosphorylation of signal transduction proteins and their molecular localisation to the TCR. By integrating high-resolution proximity- phospho-proteomic and imaging approaches using primary T cells, rather than engineered cell lines or an in vitro expanded T cell population, we uncovered transduction events previously not linked to IL-7. We show that IL-7 leads to dephosphorylation of cytohesin interacting protein (CYTIP) at a hitherto undescribed phosphorylation site (pThr280) and alters the co-localisation of cytohesin-1 with the TCR and LFA-1 integrin. These results show that IL-7, acting via CYTIP and cytohesin-1, may impact TCR activation thresholds by enhancing the co-clustering of TCR and LFA-1 integrin. Portland Press Ltd. 2022-02-11 2022-02-04 /pmc/articles/PMC8883493/ /pubmed/35015072 http://dx.doi.org/10.1042/BCJ20210313 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Immunology & Inflammation
Queiroz, Rayner M. L.
Piper, Siân C.
Rees, Johanna S.
Strickson, Sam
Briend, Emmanuel
Low, Choon Pei
Ferguson, G. John
Lilley, Kathryn S.
Jackson, Antony P.
Finch, Donna K.
Proteomic analysis in primary T cells reveals IL-7 alters T cell receptor thresholding via CYTIP/cytohesin/LFA-1 localisation and activation
title Proteomic analysis in primary T cells reveals IL-7 alters T cell receptor thresholding via CYTIP/cytohesin/LFA-1 localisation and activation
title_full Proteomic analysis in primary T cells reveals IL-7 alters T cell receptor thresholding via CYTIP/cytohesin/LFA-1 localisation and activation
title_fullStr Proteomic analysis in primary T cells reveals IL-7 alters T cell receptor thresholding via CYTIP/cytohesin/LFA-1 localisation and activation
title_full_unstemmed Proteomic analysis in primary T cells reveals IL-7 alters T cell receptor thresholding via CYTIP/cytohesin/LFA-1 localisation and activation
title_short Proteomic analysis in primary T cells reveals IL-7 alters T cell receptor thresholding via CYTIP/cytohesin/LFA-1 localisation and activation
title_sort proteomic analysis in primary t cells reveals il-7 alters t cell receptor thresholding via cytip/cytohesin/lfa-1 localisation and activation
topic Immunology & Inflammation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8883493/
https://www.ncbi.nlm.nih.gov/pubmed/35015072
http://dx.doi.org/10.1042/BCJ20210313
work_keys_str_mv AT queirozraynerml proteomicanalysisinprimarytcellsrevealsil7alterstcellreceptorthresholdingviacytipcytohesinlfa1localisationandactivation
AT pipersianc proteomicanalysisinprimarytcellsrevealsil7alterstcellreceptorthresholdingviacytipcytohesinlfa1localisationandactivation
AT reesjohannas proteomicanalysisinprimarytcellsrevealsil7alterstcellreceptorthresholdingviacytipcytohesinlfa1localisationandactivation
AT stricksonsam proteomicanalysisinprimarytcellsrevealsil7alterstcellreceptorthresholdingviacytipcytohesinlfa1localisationandactivation
AT briendemmanuel proteomicanalysisinprimarytcellsrevealsil7alterstcellreceptorthresholdingviacytipcytohesinlfa1localisationandactivation
AT lowchoonpei proteomicanalysisinprimarytcellsrevealsil7alterstcellreceptorthresholdingviacytipcytohesinlfa1localisationandactivation
AT fergusongjohn proteomicanalysisinprimarytcellsrevealsil7alterstcellreceptorthresholdingviacytipcytohesinlfa1localisationandactivation
AT lilleykathryns proteomicanalysisinprimarytcellsrevealsil7alterstcellreceptorthresholdingviacytipcytohesinlfa1localisationandactivation
AT jacksonantonyp proteomicanalysisinprimarytcellsrevealsil7alterstcellreceptorthresholdingviacytipcytohesinlfa1localisationandactivation
AT finchdonnak proteomicanalysisinprimarytcellsrevealsil7alterstcellreceptorthresholdingviacytipcytohesinlfa1localisationandactivation