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 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.
Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
Dennis J
DJ
Wu
Center for Immunology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
Wenbo
W
Zhou
Swiss Vaccine Research Institute, Epalinges, and Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
Sarah
S
Enouz
Institute for Genetic Medicine, University of Southern California, Los Angeles, California, United States of America ; Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
Valeria
V
Orrú
Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
Stephanie M
SM
Stanford
Department of Immunology, The Scripps Research Institute, La Jolla, California, United States of America.
Christian J
CJ
Maine
Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
Novella
N
Rapini
Center for Immunology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
Kristy
K
Sawatzke
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
Isaac
I
Engel
Institute for Genetic Medicine, University of Southern California, Los Angeles, California, United States of America ; Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
Edoardo
E
Fiorillo
Department of Immunology, The Scripps Research Institute, La Jolla, California, United States of America.
Linda A
LA
Sherman
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.
Mitch
M
Kronenberg
Swiss Vaccine Research Institute, Epalinges, and Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
Dietmar
D
Zehn
Center for Immunology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
Erik
E
Peterson
Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America ; Institute for Genetic Medicine, University of Southern California, Los Angeles, California, United States of America.
Nunzio
N
Bottini
D000818:Animals; D001120:Arginine / Q000235:genetics; D015551:Autoimmunity; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D020125:Mutation, Missense; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014364:Tryptophan / Q000235:genetics
D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; D014364:Tryptophan; D001120:Arginine; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22