Autophagy-independent functions of UVRAG are essential for peripheral naive T-cell homeostasis.

UV radiation resistance-associated gene (UVRAG) encodes a tumor suppressor with putative roles in autophagy, endocytic trafficking, and DNA damage repair but its in vivo role in T cells is unknown. Because conditional homozygous deletion of Uvrag in mice results in early embryonic lethality, we generated T-cell-specific UVRAG-deficient mice that lacked UVRAG expression specifically in T cells. This loss of UVRAG led to defects in peripheral homeostasis that could not be explained by the increased sensitivity to cell death and impaired proliferation observed for other autophagy-related gene knockout mice. Instead, UVRAG-deficient T-cells exhibited normal mitochondrial clearance and activation-induced autophagy, suggesting that UVRAG has an autophagy-independent role that is critical for peripheral naive T-cell homeostatic proliferation. In vivo, T-cell-specific loss of UVRAG dampened CD8(+) T-cell responses to LCMV infection in mice, delayed viral clearance, and impaired memory T-cell generation. Our data provide novel insights into the control of autophagy in T cells and identify UVRAG as a new regulator of naïve peripheral T-cell homeostasis.

Toso controls encephalitogenic immune responses by dendritic cells and regulatory T cells.

The ability to mount a strong immune response against pathogens is crucial for mammalian survival. However, excessive and uncontrolled immune reactions can lead to autoimmunity. Unraveling how the reactive versus tolerogenic state is controlled might point toward novel therapeutic strategies to treat autoimmune diseases. The surface receptor Toso/Faim3 has been linked to apoptosis, IgM binding, and innate immune responses. In this study, we used Toso-deficient mice to investigate the importance of Toso in tolerance and autoimmunity. We found that Toso(-/-) mice do not develop severe experimental autoimmune encephalomyelitis (EAE), a mouse model for the human disease multiple sclerosis. Toso(-/-) dendritic cells were less sensitive to Toll-like receptor stimulation and induced significantly lower levels of disease-associated inflammatory T-cell responses. Consistent with this observation, the transfer of Toso(-/-) dendritic cells did not induce autoimmune diabetes, indicating their tolerogenic potential. In Toso(-/-) mice subjected to EAE induction, we found increased numbers of regulatory T cells and decreased encephalitogenic cellular infiltrates in the brain. Finally, inhibition of Toso activity in vivo at either an early or late stage of EAE induction prevented further disease progression. Taken together, our data identify Toso as a unique regulator of inflammatory autoimmune responses and an attractive target for therapeutic intervention.

Bidirectional Ventricular Tachycardia in a Patient With Fulminant Myocarditis Secondary to Cardiac Sarcoidosis Mimicking Giant Cell Myocarditis.

Differentiating between sarcoidosis and giant cell myocarditis (GCM) based on clinical presentation is difficult. We present the case of a 57-year-old woman who was initially diagnosed with GCM based on endomyocardial biopsy. The patient was refractory to standard management for GCM and went on to develop bidirectional ventricular tachycardia, a finding suggestive of sarcoidosis. Unfortunately, the patient eventually needed cardiac transplantation. The explanted heart demonstrated cardiac sarcoidosis. Bidirectional ventricular tachycardia has not been demonstrated in GCM, and its presence may help in distinguishing between GCM and cardiac sarcoidosis.

La distinction entre la sarcoïdose et la myocardite à cellules géantes (MCG) fondée sur le tableau clinique est difficile. Nous présentons le cas d'une femme de 57 ans qui avait initialement reçu un diagnostic de MCG à la suite de la biopsie endomyocardique. Comme la MCG diagnostiquée chez la patiente était réfractaire à la prise en charge thérapeutique habituelle, elle a continué à souffrir de tachycardie ventriculaire bidirectionnelle, un signe évocateur de sarcoïdose. Malheureusement, la patiente a finalement eu besoin d'une transplantation cardiaque. Le cœur explanté a démontré une sarcoïdose cardiaque. Bien que la tachycardie ventriculaire bidirectionnelle n'ait pas été démontrée lors de MCG, sa présence peut aider à distinguer la MCG de la sarcoïdose cardiaque.