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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.
The 1858C>T allele of the tyrosine phosphatase PTPN22 (causing amino acid substitution R620W in encoded protein Lyp) is present in 5-10% of the North American population and is strongly associated with numerous autoimmune diseases. Although much research has been done to define how this allele potentiates autoimmunity, the influence PTPN22 and its pro-autoimmune allele has in tumor immunity is poorly defined. To interrogate the role this allele may have in the anti-tumor immune response, we used CRISPR/Cas9 to generate mice in which the ortholog of Lyp, PEP, is mutated at position 619 to produce the relevant pro-autoimmune mutation (R619W). Results of this study show that mice homozygous for this alteration (PEP-619WW) resist tumor growth as compared with wildtype mice. Consistent with these results, tumors from PEP-619WW mice have more CD45 infiltrates containing more activated CD8 T cell and CD4 T cells. Additionally, there are more cDC1 cells and less MDSCs in tumors from PEP-619WW mice. Interestingly, the tumor infiltrating PEP-619WW cDC1s have decreased PD-L1 expression compared to cDC1s from PEP-WT mice. Taken together, our data show that the pro-autoimmune allele of Ptpn22 drives a strong anti-tumor response in innate and adaptive immune cells resulting in superior control of tumors.
The 1858C>T allele of the tyrosine phosphatase PTPN22 (causing amino acid substitution R620W in encoded protein Lyp) is present in 5–10% of the North American population and is strongly associated with numerous autoimmune diseases. Although much research has been done to define how this allele potentiates autoimmunity, the influence PTPN22 and its pro-autoimmune allele has in tumor immunity is poorly defined. To interrogate the role this allele has during the anti-tumor immune response, we used CRISPR/Cas9 to generate mice in which the ortholog of Lyp, PEP, is mutated at position 619 to produce the relevant pro-autoimmune mutation (PEP-619WW) or lack Ptpn22 expression (PEP-null). Using the B16 and other tumor models, we tested the hypothesis that pleiotropic effects of the PTPN22 pro-autoimmune allele enhances tumor immunity. Results of this study show that PEP-619WW mice, but not PEP-null mice, resist tumor growth as compared with wildtype mice. Consistent with these results, tumors from PEP-619WW mice have more CD45 infiltrates containing; more activated CD8 T cell and CD4 T cells, more cDC1 cells, and less MDSCs than WT animals. Interestingly, the tumor infiltrating PEP-619WW cDC1s have lower PD-L1 expression compared to cDC1s from PEP-WT mice. Furthermore, using single-cell RNA sequencing we show that intra-tumoral myeloid cells from PEP-619WW mice have a more cytokine responsive transcriptional signature compared to PEP-WT cells. Our results suggest that a pro-autoimmune allele can be beneficial by promoting a strong anti-tumor immune response and may have a protective effect in this disease. Also, these data highlight an important difference between the PEP-null and PEP-619WW murine models during the tumor response. Supported by grants from NIH (UO1 AI130842 and T32 AI007354 27).
Theiler's murine encephalomyelitis virus (TMEV) infection of the central nervous systemis rapidly cleared in C57BL/6 mice by an anti-viral CD8 T cell response restricted by the MHC class I molecule, H-2D b . While the CD8 T cell response against neurotropic viruses is well characterized, the identity and function of the antigen presenting cell(s) involved in this process is(are) less well defined. To address this gap in knowledge, we developed a novel C57BL/6 H-2D b conditional knockout mouse that expresses an H-2D b transgene in which the transmembrane domain locus is flanked by LoxP sites. We crossed these H-2D b LoxP mice with MHC class I-deficient mice expressing Cre-recombinase under either the CD11c or LysM promoter in order to silence H-2D b restricted antigen presentation predominantly in dendritic cells or macrophages, respectively. Upon challenge with intracranial TMEV infection, we observe that CD11c+ APCs are critical for early priming of CD8 T cells against the immunodominant TMEV peptide VP2 121-130 presented in the context of the H-2D b molecule. This stands in stark contrast to later time points post TMEV infection where CD11c+ APCs appear dispensable for the activation of antigen-specific T cells; the functionality of these late-arising antiviral CD8 T cells is reflected in the restoration of viral control at later time points. These latearising CD8 T cells also retain their capacity to induce blood-brain barrier disruption. In contrast, when H-2D b restricted antigen presentation was selectively silenced in LysM+ APCs there was no overt impact on the priming of D b :VP2 121-130 epitope-specific CD8 T cells, although a modest reduction in immune cell entry into the CNS was observed. This work establishes a model system which enables critical dissection of MHC class I restricted antigen presentation to T cells, revealing cell specific and temporal features involved in the generation of antiviral CD8 T cell responses. Employing this novel system, we established CD11c+ cells as a pivotal driver of acute, but not later-arising, antiviral CD8 T cell responses against the TMEV immunodominant epitope VP2 121-130 , with functional implications both for T cell-mediated viral control and immunopathology. Class I conditional knockout mice were developed through construction of an H-2D b transgene, in which the transmembrane (TM) domain is flanked by LoxP sites. This transgene was introduced into C57BL/6 mice deficient in H-2D b and H-2K b , leaving the floxed D b as the onlyMHC class I molecule expressed by nucleated cells (Fig 1A) [33]. Crossing this transgenic mouse line with mice expressing Cre-recombinase under the CD11c, LysM, or CMV promoter, also on total MHC class I knockout backgrounds, allowed for CD11c+ cell specific, LysM+ cell specific, or ubiquitous ablation of MHC-I expression, respectively ( Fig 1B, Fig 1C, Fig 1D).Resultant mice will be referred to as CD11c D b conditional knockout (cKO), LysM D b cKO, CMV D b cKO, or Cre-littermates depending on whether the F1 generation pups inherited the...
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