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An unbiased and replicable profiling of type 1 diabetes (T1D)-specific circulating immunome at disease onset has yet to be identified due to experimental and patient selection limitations. Multicolor flow cytometry was performed on whole blood from a pediatric cohort of 107 patients with new-onset T1D, 85 relatives of T1D patients with 0-1 islet autoantibodies (pre-T1D_LR), 58 patients with celiac disease or autoimmune thyroiditis (CD_THY) and 76 healthy controls (HC). Unsupervised clustering of flow cytometry data, validated by a semi-automated gating strategy, confirmed previous findings showing selective increase of naïve CD4 T cells and plasmacytoid DCs, and revealed a decrease in CD56brightNK cells in T1D. Furthermore, a non-selective decrease of CD3+CD56+ regulatory T cells was observed in T1D. The frequency of naïve CD4 T cells at disease onset was associated with partial remission, while it was found unaltered in the pre-symptomatic stages of the disease. Thanks to a broad cohort of pediatric individuals and the implementation of unbiased approaches for the analysis of flow cytometry data, here we determined the circulating immune fingerprint of newly diagnosed pediatric T1D and provide a reference dataset to be exploited for validation or discovery purposes to unravel the pathogenesis of T1D.

Type 1 diabetes (T1D) is a chronic autoimmune disease resulting in progressive destruction of β-cells. Several factors affecting lymphocyte and antigen-presenting cells, including dendritic cells (DCs), contribute to defective maintenance of tolerance in T1D. DC-10 are a subset of human DCs involved in IL-10-mediated tolerance. A precise monitoring of DC-10 in the peripheral blood is possible thanks to the discovery of specific biomarkers. DC-10, being cells that naturally express HLA-G, may be used for the appropriate staging of the disease. By enumerating and phenotypically characterizing DC-10 in the peripheral blood of subjects at different stages of T1D development—first-degree relatives (FDRs) of T1D patients, without (Abneg) or with (Abpos) autoantibodies, T1D patients at onset, and age-matched healthy controls (HCs)—we showed that DC-10 contain a high proportion of HLA-G-expressing cells as compared with monocytes. We reported that a low frequency of DC-10 during disease development is paralleled with the increased proportion of pro-inflammatory cDC2 cells. Moreover, DC-10 number and phenotype differ from Abneg FDRs, Abpos FDRs, and T1D patients compared with HCs, and DC-10 from T1D patients express low levels of CD83. Finally, multiple regression analysis, considering DC-10 and HLA-G-related parameters, showed that Abneg FDRs are more similar to subjects with autoimmunity than to HCs. This is the first demonstration that impairment in DC-10 number and phenotype, specifically CD83 expression, is associated with risk of developing T1D, suggesting a possible use of CD83+ DC-10 to stratify individuals at risk of T1D in conjunction with classical prognostic factors.

Translational medicine works through the definition of unmet medical needs, their understanding and final resolution. In this complex and multi-disciplinary process patients have always been regarded as “end-users” or no more than “data provider.” Considering that the translational practice is nowadays highly inefficient (i.e., large intellectual and economical resources are wasted with limited impact on people health) here we propose to reverse the process: start from patients, engage them, and keep them at the center. A new partnership needs to be formed between the patients and the health care professionals, as well as the treating physicians, to make the most out of the current “health resources.” New patient-centric approaches are emerging but they remain isolated phenomena often difficult to implement. Here—with this perspective—we aim at thinking differently and learning from new experiences. We will provide some successful examples of change, and we will discuss new approaches to create a radical change in the way translational medicine is managed and how this would significantly impact people health and health care systems.

Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.

A genetic variant of the protein tyrosine phosphatase non-receptor 22 (PTPN22) is associated with a wide range of autoimmune diseases; however, the reasons behind its prevalence in the general population remain not completely understood. Recent evidence highlights an important role of autoimmune susceptibility genetic variants in conferring resistance against certain pathogens. In this study, we examined the role of PTPN22 in persistent infection in mice lacking PTPN22 infected with lymphocytic choriomeningitis virus clone 13. We found that lack of PTPN22 in mice resulted in viral clearance 30 days after infection, which was reflected in their reduced weight loss and overall improved health. PTPN22−/− mice exhibited enhanced virus-specific CD8 and CD4 T cell numbers and functionality and reduced exhausted phenotype. Moreover, mixed bone marrow chimera studies demonstrated no differences in virus-specific CD8 T cell accumulation and function between the PTPN22+/+ and PTPN22−/− compartments, showing that the effects of PTPN22 on CD8 T cells are T cell-extrinsic. Together, these findings identify a CD8 T cell-extrinsic role for PTPN22 in weakening early CD8 T cell responses to collectively promote persistence of a chronic viral infection.