Autoimmunity-associated Allele of Tyrosine Phosphatase Gene PTPN22 Enhances Anti-viral Immunity
Robin C. Orozco, Kristi Marquardt, Isaraphorn Pratumchai, I am Fatima Sheikh, Kerri Mowen †, Alain Domissy, John R. Teijaro, Linda A. Sherman
Abstract
The 1858C>T allele of the tyrosine phosphatase PTPN22 is present in 5–10% of the North American population and is strongly associated with numerous autoimmune diseases. Although research has been done to define how this allele potentiates autoimmunity, the influence PTPN22 and its pro-autoimmune allele has in anti-viral immunity remains poorly defined. Here, we use single cell RNA-sequencing and functional studies to interrogate the impact of this pro-autoimmune allele on anti-viral immunity during Lymphocytic Choriomeningitis Virus clone 13 (LCMV-cl13) infection. Mice homozygous for this allele (PEP-619WW) clear the LCMV-cl13 virus whereas wildtype (PEP-WT) mice cannot. This is associated with enhanced anti-viral CD4 T cell responses and a more immunostimulatory CD8α- cDC phenotype. Adoptive transfer studies demonstrated that PEP-619WW enhanced anti-viral CD4 T cell function through virus-specific CD4 T cell intrinsic and extrinsic mechanisms. Taken together, our data show that the pro-autoimmune allele of Ptpn22 drives a beneficial anti-viral immune response thereby preventing what is normally a chronic virus infection.
Introduction
Allelic variation in genes that regulate immune cell responses potentially impact an individual’s response to self and foreign antigens. Genome wide association studies (GWAS) have identified variants in immune-related genes that are being increasingly associated with protective or pathologic consequences during disease [1]. However, the underlying mechanism(s) through which these mutations impact disease often remain incompletely defined. The 1858C>T allele of the tyrosine phosphatase PTPN22 (causing amino acid substitution R620W) is present in 5–10% of the North American population and is strongly associated with numerous autoimmune diseases, including Type I Diabetes (T1D), rheumatoid arthritis, systemic lupus erythematosus, and others [2–10]. This alternative allele of PTPN22 is considered the highest non-HLA risk allele in autoimmunity [7,9]. This pro-autoimmune allele is known to affect innate and adaptive immune functions, including, lymphocyte activation, toll-like receptor signaling, and cytokine production in various autoimmune contexts [8,11–18]. In humans, PTPN22 encodes the protein Lyp that is expressed in all immune cells [10].
Methods
Ethics statement
All animal studies were reviewed and approved by Scripps Research Institutional Animal Care and Use Committee (IACUC) (protocol number: 06–0291) and University of Kansas (IACUC) (protocol number: 278–01).
Mice
Both males and females ranging from 6–12 weeks of age were used in this study. Animals were housed in general housing conditions at Scripps Research. We do not observe any sex-based difference in these studies with our animals. All animal studies were reviewed and approved by Scripps Research Institutional Animal Care and Use Committee (protocol number: 06–0291). C57BL/6 WT mice were originally purchased from Jackson labs, and then bred and maintained in Scripps Animal Facility.
Results
Ptpn22 alternative allele promotes LCMV-cl13 viral clearance
Mice expressing the Ptpn22 wild type allele (PEP-WT) or Ptpn22 pro autoimmune allele (PEP-619WW) were infected with LCMV-cl13. All mice lost weight within the first week of infection (Fig 1A). However, PEP-619WW mice stabilized and regained their original weight more quickly than PEP-WT mice (Fig 1A). This difference also correlated with viral titers in the serum of these animals (Fig 1B). While PEP-WT mice had detectable virus in their serum out to day 41, viral titer in PEP-619WW mice decreased by 22 days post infection (dpi) (Fig 1B). PEP-619WW did not restrict early LCMV-cl13 infection, as viral loads in both genotypes of mice were high 3 dpi in sera, lungs, livers, and kidneys (Fig 1B and 1C). By day 41, PEP-619WW mice had no detectable virus in the serum and largely cleared virus from the target organs spleen, lungs, and livers (Fig 1D). In contrast, PEP-WT mice still had detectable virus in these organs. In both strains of mice, virus was still detectable in the kidney, an organ in which it is known virus remains detectable despite clearance from other organs [22,23,30,31].
Discussion
The strong genetic link between the PTPN22 minor allele (R620W) and autoimmunity would be expected to be an evolutionary disadvantage [7]. However, an advantage in eradicating pathogens could help explain why the variant persists in the population [91,93]. Thus, it was of interest to assess the impact of the PTPN22 autoimmunity associated allele has during virus infection. Previously, using mice deficient in Ptpn22 expression (PEP-null), we demonstrated that Ptpn22 promotes T cell exhaustion, thus permitting LCMV-cl13 persistence [27]. Although some studies have found that the lack of Ptpn22 is similar in phenotype to R620W (R619W in mice) several differences have also emerged. This may be because the 620W (619W) variant does not directly affect the phosphatase activity of this enzyme [14,94,95]. Rather, the presence of tryptophan disrupts the ability of the enzyme to bind with other proteins such as CSK and TRAF3 [13,15,95]. As an example of differing consequences, whereas PEP-null mice exhibit an increased frequency and potency of Tregs as compared with WT [96], this same Treg phenotype is not observed in naïve mice bearing the Ptpn22 pro-autoimmune allele [18,97]. Despite its importance in human health, studies have not investigated whether the Ptpn22 autoimmunity associated minor allele impact anti-viral immune responses.
Acknowledgments
We thank Scripps Research and University of Kansas Flow Cytometry Core, Histology and Microscopy Core, and Vivarium staff for their expertise and assistance in this work. We also thank T. Fehr and C. Antunes (University of Kansas) for their careful reading and editing of this manuscript. Since the creation of the PEP-619WW mice, K. Mowen has passed away and is greatly missed.
Citation: Orozco RC, Marquardt K, Pratumchai I, Shaikh AF, Mowen K, Domissy A, et al. (2024) Autoimmunity-associated allele of tyrosine phosphatase gene PTPN22 enhances anti-viral immunity. PLoS Pathog 20(3): e1012095. https://doi.org/10.1371/journal.ppat.1012095
Editor: Zia Rahman, Thomas Jefferson University, UNITED STATES
Received: April 26, 2023; Accepted: March 4, 2024; Published: March 21, 2024
Copyright: © 2024 Orozco et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Data used in this manuscript is uploaded to Dryad Repository (DOI: 10.5061/dryad.msbcc2g55). RNA sequencing data is available at GEO Accession number: GSE255614) https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE255614).
Funding: Research reported in this publication was supported by the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health under award number P20GM113117 (awarded to R.C.O, while at University of Kansas) and NIH U01 AI130842 (awarded to L.A.S) and NIH T32 AI007354 27 (fellowship to support R.C.O, while at Scripps). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1012095#abstract1
