were inadvertently omitted from the author list. The correct author and affiliations list is above. The updated author contributions section is below.MRS performed experiments, analyzed the data, and wrote the first draft of the manuscript. SK, CG, TR, IFW, SL, KA, and WF performed experiments and were involved in data analysis. PMG and MGG were involved in vector design and subcloning. DJR and XD generated PTPN22-619W mice. HDB and EC performed experiments in keratinocytes and were involved in data analysis and interpretation. FM and BB performed experiments. ACC corrected and approved the manuscript. SS, SRV, MF, GR, and MS were involved in acquisition of patient samples. MS and GR conceived, designed, and supervised the study. All authors wrote, corrected, and approved the manuscript.The authors regret the errors.

Loss-of-function variants within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with increased risk for Crohn's disease (CD). A disturbed regulation of T helper (Th) cell responses causing loss of tolerance against self- or commensal-derived antigens and an altered intestinal microbiota plays a pivotal role in CD pathogenesis. Loss of PTPN2 in the T-cell compartment causes enhanced induction of Th1 and Th17 cells, but impaired induction of regulatory T cells (Tregs) in several mouse colitis models, namely acute and chronic dextran sodium sulfate colitis, and T-cell transfer colitis models. This results in increased susceptibility to intestinal inflammation and intestinal dysbiosis which is comparable with that observed in CD patients. We detected inflammatory infiltrates in liver, kidney, and skin and elevated autoantibody levels indicating systemic loss of tolerance in PTPN2-deficient animals. CD patients featuring a loss-of-function PTPN2 variant exhibit enhanced Th1 and Th17 cell, but reduced Treg markers when compared with PTPN2 wild-type patients in serum and intestinal tissue samples. Our data demonstrate that dysfunction of PTPN2 results in aberrant T-cell differentiation and intestinal dysbiosis similar to those observed in human CD. Our findings indicate a novel and crucial role for PTPN2 in chronic intestinal inflammation.

Immunotherapies to treat cancer have achieved remarkable successes, but major challenges persist. An inherent weakness of current treatment approaches is that therapeutically targeted pathways are not only found in tumors, but also in tissue microenvironments, particularly inflamed tissues. This confounding overlap complicates treatment as well as predictions of treatment outcome. In an effort to identify potential tumor-unique immunotherapeutic targets that are distinct from general tissue inflammation, we used complementary single-cell analysis approaches to interrogate immune cell alterations and interactions in human squamous cell carcinomas and site-matched non-malignant, inflamed tissues. We found that a distinct population of intratumoral regulatory T cells (Tregs) received T cell receptor (TCR) signals from antigen-presenting cells and this Treg population was uniquely identified by co-expression of ICOS and IL-1 receptor type 1 (IL-1R1). Intratumoral IL-1R+ Tregs appeared activated and a TCR signal was sufficient to convert IL-1R1- Tregs to IL-1R1+ Tregs ex vivo. Overall, our work identifies an intratumoral Treg population that recognizes antigen in the tumor microenvironment and two biomarkers that allow for specific depletion of these Tregs. Finally, our approach also provides a blueprint for extricating tumor-unique therapeutic targets distinct from general inflammatory patterns in other tumors.

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