Nonobese diabetic (NOD) mice are a widely used animal model to study mechanisms leading to autoimmune diabetes. A gluten-free diet reduces and delays the incidence of diabetes in NOD mice, but the underlying mechanisms remain largely unknown. In this study, we performed single-cell transcriptomic and flow cytometry analysis of T cells and innate lymphocytes in the spleen and pancreatic lymph nodes of NOD mice fed a gluten-free or standard diet. We observed that the gluten-free diet did not induce a substantial alteration in the abundance or phenotype of any lymphocyte subset that would directly explain its protective effect against diabetes. However, the gluten-free diet induced subtle changes in the differentiation of subsets with previously proposed protective roles in diabetes development, such as Tregs, activated γδT cells, and NKT cells. Globally, the gluten-free diet paradoxically promoted activation and effector differentiation across multiple subpopulations and induced genes regulated by IL-2, IL-7, and IL-15. In contrast, the standard diet induced type I interferon-responsive genes. Overall, the gluten-free diet might prevent diabetes in NOD mice by inducing small-scale changes in multiple cell types rather than acting on a specific lymphocyte subset.

• Keywords
• NOD mice, T regulatory cells, gluten‐free diet, single‐cell transcriptomics, type I diabetes,
• MeSH
• Lymphocyte Activation immunology   MeSH
• Diet, Gluten-Free * MeSH
• Cell Differentiation MeSH
• Diabetes Mellitus, Type 1 * immunology   MeSH
• Mice, Inbred NOD MeSH
• Mice MeSH
• T-Lymphocyte Subsets * immunology   MeSH
• Transcriptome MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Lck, a member of the Src kinase family, is a non-receptor tyrosine kinase involved in immune cell activation, antigen recognition, tumor growth, and cytotoxic response. The enzyme has usually been linked to T lymphocyte activation upon antigen recognition. Lck activation is central to CD4, CD8, and NK activation. However, recently, it has become clearer that activating the enzyme in CD8 cells can be independent of antigen presentation and enhance the cytotoxic response. The role of Lck in NK cytotoxic function has been controversial in a similar fashion as the role of the enzyme in CAR T cells. Inhibiting tyrosine kinases has been a highly successful approach to treating hematologic malignancies. The inhibitors may be useful in treating other tumor types, and they may be useful to prevent cell exhaustion. New, more selective inhibitors have been documented, and they have shown interesting activities not only in tumor growth but in the treatment of autoimmune diseases, asthma, and graft vs. host disease. Drug repurposing and bioinformatics can aid in solving several unsolved issues about the role of Lck in cancer. In summary, the role of Lck in immune response and tumor growth is not a simple event and requires more research.

• Keywords
• CAR-T cell, Lck, NK cytotoxicity, Src kinases, T-cell cytotoxicity, cell adhesion, cell proliferation, hematologic tumors, solid tumors,
• Publication type
• Journal Article MeSH
• Review MeSH