The widely used nonobese diabetic (NOD) mouse model of autoimmune (Type 1) diabetes mellitus shares multiple characteristics with the human disease, and studies employing this model continue to yield clinically relevant and important information. Here, we review some of the recent key findings obtained from NOD mouse investigations that have both advanced our understanding of disease pathogenesis and suggested new therapeutic targets and approaches. Areas discussed include antigen discovery, identification of genes and pathways contributing to disease susceptibility, development of strategies to image islet inflammation and the testing of therapeutics. We also review recent technical advances that, combined with an improved understanding of the NOD mouse model’s limitations, should work to ensure its popularity, utility and relevance in the years ahead.

authors note that in Fig. 2, the ''myosin VI'' labels should be replaced with ''vinculin'' in D and with ''R-Tfn'' in E. The corrected figure and its legend appear below. In addition, the portion of the

Purpose: To assess the potential for CUE-101, a novel therapeutic fusion protein, to selectively activate and expand HPV16 E7 11-20-specific CD8 þ T cells as an off-the shelf therapy for the treatment of HPV16-driven tumors, including head and neck squamous cell carcinoma (HNSCC), cervical, and anal cancers. Experimental Design: CUE-101 is an Fc fusion protein composed of a human leukocyte antigen (HLA) complex, an HPV16 E7 peptide epitope, reduced affinity human IL2 molecules, and an effector attenuated human IgG1 Fc domain. Human E7-specific T cells and human peripheral blood mononuclear cells (PBMC) were tested to demonstrate cellular activity and specificity of CUE-101, whereas in vivo activity of CUE-101 was assessed in HLA-A2 transgenic mice. Antitumor efficacy with a murine surrogate (mCUE-101) was tested in the TC-1 syngeneic tumor model. Results: CUE-101 demonstrates selective binding, activation, and expansion of HPV16 E7 11-20-specific CD8 þ T cells from PBMCs relative to nontarget cells. Intravenous administration of CUE-101 induced selective expansion of HPV16 E7 11-20-specific CD8 þ T cells in HLA-A2 (AAD) transgenic mice, and anticancer efficacy and immunologic memory was demonstrated in TC-1 tumor-bearing mice treated with mCUE-101. Combination therapy with anti-PD-1 checkpoint blockade further enhanced the observed efficacy. Conclusions: Consistent with its design, CUE-101 demonstrates selective expansion of an HPV16 E7 11-20-specific population of cytotoxic CD8 þ T cells, a favorable safety profile, and in vitro and in vivo evidence supporting its potential for clinical efficacy in an ongoing phase I trial (NCT03978689).

The immune system’s ability to recognize peptides on major histocompatibility molecules (pMHCs) contributes to eradication of cancers and pathogens. Tracking these responses in vivo could help evaluate the efficacy of immune interventions and improve mechanistic understanding of immune responses. We employ synTacs, dimeric pMHC scaffolds of defined composition, which enable clonal-selective delivery of a variety of signaling, recruitment, and imaging modalities. We show that synTacs, when labeled with positron-emitting isotopes, can non-invasively image antigen-specific CD8 T cells in vivo . We imaged human papillomavirus (HPV16) E7-specific CD8 T cells by positron emission tomography with an HPV16 E7 peptide-loaded synTac in HPV16-positive tumors, following administration of a therapeutic vaccine. We also imaged influenza A virus (IAV) nucleoprotein-specific CD8 T cells in the lungs of IAV-infected mice, using an isotopically labeled flu-specific synTac. It is thus possible to visualize antigen-specific CD8 T cell populations in vivo , which may serve prognostic and diagnostic roles.

Peptide-MHC (pMHC) multimers, in addition to being tools for tracking and quantifying antigen-specific T cells, can mediate downstream signaling after T-cell receptor engagement. In the absence of costimulation, this can lead to anergy or apoptosis of cognate T cells, a property that could be exploited in the setting of autoimmune disease. Most studies with class I pMHC multimers used noncovalently linked peptides, which can allow unwanted CD8 + T-cell activation as a result of peptide transfer to cellular MHC molecules. To circumvent this problem, and given the role of self-reactive CD8 + T cells in the development of type 1 diabetes, we designed a single-chain pMHC complex (scK d .IGRP) by using the class I MHC molecule H-2K d and a covalently linked peptide derived from islet-specific glucose-6-phosphatase catalytic subunit-related protein ), a well established autoantigen in NOD mice. X-ray diffraction studies revealed that the peptide is presented in the groove of the MHC molecule in canonical fashion, and it was also demonstrated that scK d .IGRP tetramers bound specifically to cognate CD8 + T cells. Tetramer binding induced death of naive T cells and in vitro-and in vivo-differentiated cytotoxic T lymphocytes, and tetramer-treated cytotoxic T lymphocytes showed a diminished IFN-γ response to antigen stimulation. Tetramer accessibility to disease-relevant T cells in vivo was also demonstrated. Our study suggests the potential of single-chain pMHC tetramers as possible therapeutic agents in autoimmune disease. Their ability to affect the fate of naive and activated CD8 + T cells makes them a potential intervention strategy in early and late stages of disease.