DEC-205-mediated antigen targeting to steady-state dendritic cells induces deletion of diabetogenic CD8⁺ T cells independently of PD-1 and PD-L1.

CD8⁺ T cells specific for islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) have been implicated in type 1 diabetes in both humans and non-obese diabetic (NOD) mice, in which T cells specific for IGRP206₋214 are highly prevalent. We sought to manipulate these pathogenic T cells by exploiting the ability of steady-state dendritic cells (DCs) to present antigens in a tolerogenic manner. The endocytic receptor DEC-205 was utilized to deliver an IGRP206₋214 mimotope to DCs in NOD mice, and the impact of this delivery on a polyclonal population of endogenous islet-reactive cognate T cells was determined. Assessment of islet-infiltrating CD8⁺ T cells showed a decrease in the percentage, and the absolute number, of endogenous IGRP206₋214-specific T cells when the mimotope was delivered to DCs, compared with delivery of a specificity control. Employing an adoptive transfer system, deletion of CD8⁺ T cells as a result of DEC-205-mediated antigen targeting was found to occur independently of programmed death-1 (PD-1) and its ligand (PD-L1), both often implicated in the regulation of peripheral T-cell tolerance. Given its promise for the manipulation of self-reactive polyclonal T cells demonstrated here, the distinctive characteristics of this antigen delivery system will be important to appreciate as its potential as an intervention for autoimmune diseases continues to be investigated.

T-cell autoantigens in the non-obese diabetic mouse model of autoimmune diabetes.

The non-obese diabetic (NOD) mouse model of autoimmune (type 1) diabetes has contributed greatly to our understanding of disease pathogenesis and has facilitated the development and testing of therapeutic strategies to combat the disease. Although the model is a valuable immunological tool in its own right, it reaches its fullest potential in areas where its findings translate to the human disease. Perhaps the foremost example of this is the field of T-cell antigen discovery, from which diverse benefits can be derived, including the development of antigen-specific disease interventions. The majority of NOD T-cell antigens are also targets of T-cell autoimmunity in patients with type 1 diabetes, and several of these are currently being evaluated in clinical trials. Here we review the journeys of these antigens from bench to bedside. We also discuss several recently identified NOD T-cell autoantigens whose translational potential warrants further investigation.

An Unusual Case of Metastatic Functional Thyroid Carcinoma With a Remarkable Treatment Response to Radioactive Iodine.

Functional thyroid carcinoma is an unusual cause of thyrotoxicosis. We describe the clinical presentation and treatment of a patient with thyrotoxicosis due to functional thyroid carcinoma and Graves disease, and discuss potential mechanisms causing the thyrotoxicosis. A 79-year-old woman with a remote history of hemithyroidectomy and current hyperthyroidism came to the hospital with upper and lower extremity weakness. Hospital evaluation revealed a suppressed thyroid-stimulating hormone (TSH) level, positive test for thyroid-stimulating immunoglobulins, as well as a thyroid nodule, lung masses, and a 4.4-cm gluteal mass. Fine-needle aspiration of the gluteal mass revealed metastatic differentiated thyroid carcinoma. Even after completion thyroidectomy and excision of her gluteal mass, her hyperthyroid status continued when she was not receiving levothyroxine. A radioactive iodine uptake and scan revealed unusually high lung uptake of 40%, and she was successfully treated with radioactive iodine (RAI) despite complete TSH suppression. The patient developed hypothyroidism 2 months after RAI administration; 6 months after RAI administration, her thyroglobulin (Tg) levels had fallen from a peak of 1976 ng/mL to 1.4 ng/mL. She had no anti-Tg antibodies. Repeated positron emission tomography-computed tomography nearly 1 year after RAI treatment shows substantial regression in the lung nodules, and Tg measured by mass spectroscopy is undetectable. This case demonstrates that thyrotoxicosis in the setting of metastatic thyroid carcinoma may be the result of functional thyroid carcinoma and may be successfully treated with selective surgery and RAI administration.