Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive T cells.
A C1858T (R620W) variation in the PTPN22 gene encoding the tyrosine phosphatase LYP is a major risk factor for human autoimmunity. LYP is a known negative regulator of signaling through the T cell receptor (TCR), and murine Ptpn22 plays a role in thymic selection. However, the mechanism of action of...
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doaj-7c8c18f1111346f0b9493e777b87dcf62020-11-24T21:52:05ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0192e8667710.1371/journal.pone.0086677Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive T cells.Dennis J WuWenbo ZhouSarah EnouzValeria OrrúStephanie M StanfordChristian J MaineNovella RapiniKristy SawatzkeIsaac EngelEdoardo FiorilloLinda A ShermanMitch KronenbergDietmar ZehnErik PetersonNunzio BottiniA C1858T (R620W) variation in the PTPN22 gene encoding the tyrosine phosphatase LYP is a major risk factor for human autoimmunity. LYP is a known negative regulator of signaling through the T cell receptor (TCR), and murine Ptpn22 plays a role in thymic selection. However, the mechanism of action of the R620W variant in autoimmunity remains unclear. One model holds that LYP-W620 is a gain-of-function phosphatase that causes alterations in thymic negative selection and/or thymic output of regulatory T cells (Treg) through inhibition of thymic TCR signaling. To test this model, we generated mice in which the human LYP-W620 variant or its phosphatase-inactive mutant are expressed in developing thymocytes under control of the proximal Lck promoter. We found that LYP-W620 expression results in diminished thymocyte TCR signaling, thus modeling a "gain-of-function" of LYP at the signaling level. However, LYP-W620 transgenic mice display no alterations of thymic negative selection and no anomalies in thymic output of CD4(+)Foxp3(+) Treg were detected in these mice. Lck promoter-directed expression of the human transgene also causes no alteration in thymic repertoire or increase in disease severity in a model of rheumatoid arthritis, which depends on skewed thymic selection of CD4(+) T cells. Our data suggest that a gain-of-function of LYP is unlikely to increase risk of autoimmunity through alterations of thymic selection and that LYP likely acts in the periphery perhaps selectively in regulatory T cells or in another cell type to increase risk of autoimmunity.http://europepmc.org/articles/PMC3911918?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Dennis J Wu Wenbo Zhou Sarah Enouz Valeria Orrú Stephanie M Stanford Christian J Maine Novella Rapini Kristy Sawatzke Isaac Engel Edoardo Fiorillo Linda A Sherman Mitch Kronenberg Dietmar Zehn Erik Peterson Nunzio Bottini |
spellingShingle |
Dennis J Wu Wenbo Zhou Sarah Enouz Valeria Orrú Stephanie M Stanford Christian J Maine Novella Rapini Kristy Sawatzke Isaac Engel Edoardo Fiorillo Linda A Sherman Mitch Kronenberg Dietmar Zehn Erik Peterson Nunzio Bottini Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive T cells. PLoS ONE |
author_facet |
Dennis J Wu Wenbo Zhou Sarah Enouz Valeria Orrú Stephanie M Stanford Christian J Maine Novella Rapini Kristy Sawatzke Isaac Engel Edoardo Fiorillo Linda A Sherman Mitch Kronenberg Dietmar Zehn Erik Peterson Nunzio Bottini |
author_sort |
Dennis J Wu |
title |
Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive T cells. |
title_short |
Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive T cells. |
title_full |
Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive T cells. |
title_fullStr |
Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive T cells. |
title_full_unstemmed |
Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive T cells. |
title_sort |
autoimmunity-associated lyp-w620 does not impair thymic negative selection of autoreactive t cells. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2014-01-01 |
description |
A C1858T (R620W) variation in the PTPN22 gene encoding the tyrosine phosphatase LYP is a major risk factor for human autoimmunity. LYP is a known negative regulator of signaling through the T cell receptor (TCR), and murine Ptpn22 plays a role in thymic selection. However, the mechanism of action of the R620W variant in autoimmunity remains unclear. One model holds that LYP-W620 is a gain-of-function phosphatase that causes alterations in thymic negative selection and/or thymic output of regulatory T cells (Treg) through inhibition of thymic TCR signaling. To test this model, we generated mice in which the human LYP-W620 variant or its phosphatase-inactive mutant are expressed in developing thymocytes under control of the proximal Lck promoter. We found that LYP-W620 expression results in diminished thymocyte TCR signaling, thus modeling a "gain-of-function" of LYP at the signaling level. However, LYP-W620 transgenic mice display no alterations of thymic negative selection and no anomalies in thymic output of CD4(+)Foxp3(+) Treg were detected in these mice. Lck promoter-directed expression of the human transgene also causes no alteration in thymic repertoire or increase in disease severity in a model of rheumatoid arthritis, which depends on skewed thymic selection of CD4(+) T cells. Our data suggest that a gain-of-function of LYP is unlikely to increase risk of autoimmunity through alterations of thymic selection and that LYP likely acts in the periphery perhaps selectively in regulatory T cells or in another cell type to increase risk of autoimmunity. |
url |
http://europepmc.org/articles/PMC3911918?pdf=render |
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