Biology subjects

Utz, P.

Publications and source records attributed to Utz, P..

3 recordsLinked to original sources

bioRxiv2026

Targeted depletion of CD38+ autoreactive T cells prevents type 1 diabetes

Type 1 diabetes (T1D) is caused by T cell-mediated autoimmune destruction of insulin-producing islet {beta}-cells. Treatment with T-cell depleting therapies delays the progression of stage 2 and 3 T1D, but these agents exert broad immunosuppressive effects on T cell populations, including T regulatory cells (Tregs), which are key in promoting immune tolerance. We evaluated non-obese diabetic (NOD) mice and recently diagnosed T1D patients and identified CD38 as a marker for pathogenic T cell populations. Using adoptive T-cell transfer in Recombination Activating Gene 1 knockout NOD mice and in a humanized mouse model of autoimmune diabetes, we demonstrated that CD38-expressing autoreactive T cells drive diabetes pathogenesis. Furthermore, we found that selective depletion of CD38+ cells, using an anti-CD38 monoclonal antibody (mAb), prevents insulitis and diabetes onset without depleting CD4+CD25+ Tregs. Administration of anti-CD38 mAb did not adversely affect islet function and may selectively eliminate immunogenic senescent islet {beta}-cells. These results support the strategy of selectively depleting diabetogenic T cells using an anti-CD38 mAb to treat T1D and restore immune tolerance. Therefore, transient depletion of autoreactive T cells using anti-CD38 mAb may provide a novel strategy to prevent or abrogate {beta}-cell autoimmunity in T1D. One sentence summaryPathogenic autoreactive are characterized by CD38 overexpression, and their selective depletion with anti-CD38 monoclonal antibody prevents autoimmune diabetes.

immunology↗

bioRxiv2023

Disease Tolerance Acquired Through Repeated Plasmodium Infection Involves Epigenetic Reprogramming of Innate Immune Cells

The regulation of inflammation is a critical aspect of disease tolerance and naturally acquired immunity to malaria. Here, we demonstrate using RNA sequencing and epigenetic landscape profiling by cytometry by Time-Of-Flight (EpiTOF), that the regulation of inflammatory pathways during asymptomatic parasitemia occurs downstream of pathogen sensing--at the epigenetic level. The abundance of certain epigenetic markers (methylation of H3K27 and dimethylation of arginine residues) and decreased prevalence of histone variant H3.3 correlated with suppressed cytokine responses among monocytes of Ugandan children. Such an epigenetic signature was observed across diverse immune cell populations and not only characterized active asymptomatic parasitemia but also predicted long-term future disease tolerance when observed in uninfected children. This broad methylated signature likely develops gradually and was associated with age and recent parasite exposure. Our data support a model whereby exposure to Plasmodium falciparum induces epigenetic changes that regulate excessive inflammation and contribute to naturally acquired immunity to malaria.

immunology↗

bioRxiv2021

Human KIR+CD8+ T cells target pathogenic T cells in Celiac disease and are active in autoimmune diseases and COVID-19

Previous reports show that Ly49+CD8+ T cells can suppress autoimmunity in mouse models of autoimmune diseases. Here we find a markedly increased frequency of CD8+ T cells expressing inhibitory Killer cell Immunoglobulin like Receptors (KIR), the human equivalent of the Ly49 family, in the blood and inflamed tissues of various autoimmune diseases. Moreover, KIR+CD8+ T cells can efficiently eliminate pathogenic gliadin-specific CD4+ T cells from Celiac disease (CeD) patients leukocytes in vitro. Furthermore, we observe elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 and influenza-infected patients, and this correlates with disease severity and vasculitis in COVID-19. Expanded KIR+CD8+ T cells from these different diseases display shared phenotypes and similar T cell receptor sequences. These results characterize a regulatory CD8+ T cell subset in humans, broadly active in both autoimmune and infectious diseases, which we hypothesize functions to control self-reactive or otherwise pathogenic T cells. One-Sentence SummaryHere we identified KIR+CD8+ T cells as a regulatory CD8+ T cell subset in humans that suppresses self-reactive or otherwise pathogenic CD4+ T cells.

immunology↗