Autoimmunity-associated allele of tyrosine phosphatase gene PTPN22 enhances anti-viral immunity

• Published in: PLoS pathogens Vol. 20; no. 3; p. e1012095
• Main Authors: Orozco, Robin C, Marquardt, Kristi, Pratumchai, Isaraphorn, Shaikh, Anam Fatima, Mowen, Kerri, Domissy, Alain, Teijaro, John R, Sherman, Linda A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.03.2024; Public Library of Science (PLoS)
• Subjects: Adoptive transfer; Alleles; Allelomorphism; Analysis; Animals; Antiviral agents; Autoimmune diseases; Autoimmune Diseases - genetics; Autoimmunity; Autoimmunity - genetics; B cells; Biology and life sciences; CD4 antigen; Chronic infection; Cloning; Dendritic cells; Dosage and administration; Gene expression; Gene sequencing; Genome-wide association studies; Health aspects; Immune response; Immune system; Immunity; Immunostimulation; Infection; Infections; Kinases; Lymphocytes; Lymphocytes T; Lymphocytic Choriomeningitis; Medical research; Medicine and health sciences; Medicine, Experimental; Mice; Neutrophils; Phenols; Phenotypes; Phosphatase; Phosphatases; Phosphoric Monoester Hydrolases - genetics; Protein-tyrosine-phosphatase; Research and Analysis Methods; Spleen; T cell receptors; T cells; Tyrosine; Viruses; Canada; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1012095

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.