Proautoimmune Allele of Tyrosine Phosphatase, PTPN22, Enhances Tumor Immunity

Abstract

R.C.O. conceptualized, designed, and performed experiments; analyzed results; and wrote and edited the manuscript. K. Marquardt provided reagents, bred and genotyped mice, and performed experiments. K. Mowen was the principal investigator whose laboratory generated the PEP-619WW mice on the C57BL/6 background. L.A.S. conceptualized and designed experiments, reviewed data, and wrote and edited the manuscript.

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

“…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.…”

“…C57BL/6 WT mice were originally purchased from Jackson labs, and then bred and maintained in Scripps Animal Facility. Ptpn22 R619W (PEP-619WW) mice were generated using CRISPR/Cas9 technology on a C57BL/6 background using methods previously reported [ 97 , 103 ] in the Mowen Lab. In short, four nucleotides were replaced on exon 14 of Ptpn22 to insert the BspEI restriction site and cause an arginine (R) to tryptophan (W) amino acid substitution at amino acid position 619.…”

Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders

“…B16-OVA tumours of PTPN22-R619W-mutant mice display enhanced expression of markers of T cell and myeloid cell activation and enhanced infiltration of type 1 conventional dendritic cells 209 . However, no significant differences were observed between PTPN22-R619W-mutant and wild-type mice in the control of poorly immunogenic LLC and B16-F10 tumour growth 209 .…”

“…Mice carrying homozygous R619W knock-in alteration (homologous to the human autoimmune-associated R620W alteration) display enhanced control of xenografted Hepa1-6.x1 tumour growth compared with wild-type mice, although are less effective at controlling tumour growth than mice that lack PTPN22 (refs. 208 , 209 ). PTPN22-R619W-mutant mice also show significantly greater control of xenografted immunogenic B16-OVA tumours — but not mice that lack adaptive immunity — and immunogenic MC38 tumours, with enhanced tumour immune cell infiltration in both models 209 .…”

“… 208 , 209 ). PTPN22-R619W-mutant mice also show significantly greater control of xenografted immunogenic B16-OVA tumours — but not mice that lack adaptive immunity — and immunogenic MC38 tumours, with enhanced tumour immune cell infiltration in both models 209 . B16-OVA tumours of PTPN22-R619W-mutant mice display enhanced expression of markers of T cell and myeloid cell activation and enhanced infiltration of type 1 conventional dendritic cells 209 .…”