Intravital visualization of autoimmune-induced tissue damage and Treg cell protection shows contact-based immune cell interactions and growth of bystander tissue cells in pancreatic islet grafts.

Aims: Research into the relationship between pathogens, faecal indicator microbes and environmental factors in beach sand has been limited, yet vital to the understanding of the microbial relationship between sand and the water column and to the improvement of criteria for better human health protection at beaches. The objectives of this study were to evaluate the presence and

IL-2R signaling is essential for regulatory T cell (Treg) function. However, the precise contribution of IL-2 during Treg thymic development, peripheral homeostasis and lineage stability remains unclear. Here we show that IL-2R signaling is required by thymic Tregs at an early step for expansion and survival, and a later step for functional maturation. Using inducible, conditional deletion of CD25 in peripheral Tregs, we also find that IL-2R signaling is indispensable for Treg homeostasis, whereas Treg lineage stability is largely IL-2-independent. CD25 knockout peripheral Tregs have increased apoptosis, oxidative stress, signs of mitochondrial dysfunction, and reduced transcription of key enzymes of lipid and cholesterol biosynthetic pathways. A divergent IL-2R transcriptional signature is noted for thymic Tregs versus peripheral Tregs. These data indicate that IL-2R signaling in the thymus and the periphery leads to distinctive effects on Treg function, while peripheral Treg survival depends on a non-conventional mechanism of metabolic regulation.

CTLA4 insufficiency is genetically associated with stomach cancer. Miska et al. demonstrate that CTLA4 insufficiency causes stomach cancer by autoimmune inflammation, an effect largely attributed to type 2 cytokine stimulation of stomach mucosal cells. These findings suggest preventive strategies against tumor initiation by controlling type 2 inflammation while preserving type 1 immunity.

SUMMARY CD4 and CD8 T-cell lineages differentiate through respective thymic selection processes. Here we report cross-differentiation from the CD8 lineage to CD4 T cells, but not vice versa, predominantly in the large-intestine-associated microenvironment. It occurred in the absence or distal presence of cognate antigens. This pathway produced MHC-class-I-restricted CD4+Foxp3+ Treg (CI-Treg) cells. Blocking T-cell-intrinsic TGFβ signaling diminished CI-Treg populations in lamina propria but did not preclude the CD8-to-CD4 conversion. Microbiota were not required for the cross-differentiation but presence of microbiota led to expansion of the converted CD4 T-cell population in the large intestine. CI-Treg cells did not promote tolerance to microbiota per se, but regulated systemic homeostasis of T lymphocytes and protected the large intestine from inflammatory damage. Overall, the clonal conversion from the CD8 lineage to CD4 T-cell subsets occurred regardless of “self” or “nonself”. This lineage plasticity may promote “selfless” tolerance for immune balance.