Macroautophagy was recently shown to regulate both lymphocyte biology and innate immunity. In this study we sought to determine whether a deregulation of autophagy was linked to the development of autoimmunity. Genome-wide association studies have pointed out nucleotide polymorphisms that can be associated with systemic lupus erythematosus, but the potential role of autophagy in the initiation and/or development of this syndrome is still unknown. Here, we provide first clues of macroautophagy deregulation in lupus. By the use of LC3 conversion assays and electron microscopy experiments, we observed that T cells from two distinct lupus-prone mouse models, i.e., MRLlpr/lpr and (NZB/NZW)F1, exhibit high loads of autophagic compartments compared with nonpathologic control CBA/J and BALB/c mice. Unlike normal mice, autophagy increases with age in murine lupus. In vivo lipopolysaccharide stimulation in CBA/J control mice efficiently activates T lymphocytes but fails to upregulate formation of autophagic compartments in these cells. This argues against a deregulation of autophagy in lupus T cells solely resulting from an acute inflammation injury. Autophagic vacuoles quantified by electron microscopy are also found to be significantly more frequent in T cells from lupus patients compared with healthy controls and patients with non-lupus autoimmune diseases. This elevated number of autophagic structures is not distributed homogeneously and appears to be more pronounced in certain T cells. These results suggest that autophagy could regulate the survival of autoreactive T cell during lupus, and could thus lead to design new therapeutic options for lupus.

To gain new insight into the role of B-cell autophagy, we generated two novel mouse models deficient for the autophagy-related gene (Atg)5, one from the outset pro-B cell stage (Atg5 f/ − Mb1 cre) and the other in mature B cells only (Atg5 f/ − CD21 cre). We show that autophagy is dispensable for pro-to pre-B cell transition, but necessary at a basal level to maintain normal numbers of peripheral B cells. It appears non-essential for B-cell activation under B-cell receptor stimulation but required for their survival after lipopolysaccharide stimulation that drives plasmablast differentiation and for specific IgM production after immunization. Results obtained using Atg5 f/ − CD21 cre × C57BL/6 lpr/lpr autoimmune-prone mice show that B-cell autophagy is involved in the maintenance of anti-nuclear antibody secretion, elevated number of long-lived plasma cells, and sustains IgG deposits in the kidneys. Thus, treatments specifically targeting autophagy might be beneficial in systemic autoimmune diseases. Cell Death and Differentiation (2016) 23, 853-864; doi:10.1038/cdd.2015 published online 20 November 2015 Macroautophagy is a catabolic process allowing the degradation of cytoplasmic material in double membrane vesicles, ultimately fusing with lysosomes. Macroautophagy, initially implicated in the generation of nutrients under metabolic stress, is known to have multiple roles, in different physiologic compartments, such as in vacuole trafficking, cell signalling, and cell death. Macroautophagy is deeply involved in the regulation of immunity.1 It has been shown that autophagy can regulate inflammation related to inflammasome activation and to type I interferon secretion. Moreover, it contributes to antigen presentation by both major histocompatibility complex (MHC) class I and class II molecules. 2Macroautophagy is also tightly linked to lymphocyte activation and survival. It has central roles in T-cell basal homeostasis, survival, and polarization.3 It is also involved in the regulation of T-cell signalling by downregulating the NF-κB pathway 4 and apoptosis processes through the procaspases 3 and 8 degradation. 5 Macroautophagy has additionally been described to regulate B-cell lineage, in particular during B-cell development. Thus, it has been shown that B cells generated from fetal liver chimaeras, with a complete deletion of the essential autophagy-related gene (Atg)5, exhibited a block at the proto pre-B stage transition.6,7 However, as the genetic deletion is systemic and occurs very early during development, the question remains over whether the developmental blockade could be due to defects resulting from early haematopoietic development. Indeed, macroautophagy has been shown to be fundamental to haematopoietic stem cell survival and renewal.8 Moreover, conditional deletion of Atg5 under the control of CD19 promoter expressed from the pre-B stage does not lead to major developmental breaks, except a decrease in B-1a B-cell population. 6 The contrast with results obtained with chimaeric mice could be due...

Antiviral immunity in the model organism Drosophila melanogaster involves the broadly active intrinsic mechanism of RNA interference (RNAi) and virus-specific inducible responses. Here, using a panel of six viruses, we investigated the role of hemocytes and autophagy in the control of viral infections. Injection of latex beads to saturate phagocytosis, or genetic depletion of hemocytes, resulted in decreased survival and increased viral titers following infection with Cricket paralysis virus (CrPV), Flock House virus (FHV), and vesicular stomatitis virus (VSV) but had no impact on Drosophila C virus (DCV), Sindbis virus (SINV), and Invertebrate iridescent virus 6 (IIV6) infection. In the cases of CrPV and FHV, apoptosis was induced in infected cells, which were phagocytosed by hemocytes. In contrast, VSV did not trigger any significant apoptosis but we confirmed that the autophagy gene Atg7 was required for full virus resistance, suggesting that hemocytes use autophagy to recognize the virus. However, this recognition does not depend on the Toll-7 receptor. Autophagy had no impact on DCV, CrPV, SINV, or IIV6 infection and was required for replication of the sixth virus, FHV. Even in the case of VSV, the increases in titers were modest in Atg7 mutant flies, suggesting that autophagy does not play a major role in antiviral immunity in Drosophila. Altogether, our results indicate that, while autophagy plays a minor role, phagocytosis contributes to virus-specific immune responses in insects. IMPORTANCEPhagocytosis and autophagy are two cellular processes that involve lysosomal degradation and participate in Drosophila immunity. Using a panel of RNA and DNA viruses, we have addressed the contribution of phagocytosis and autophagy in the control of viral infections in this model organism. We show that, while autophagy plays a minor role, phagocytosis contributes to virusspecific immune responses in Drosophila. This work brings to the front a novel facet of antiviral host defense in insects, which may have relevance in the control of virus transmission by vector insects or in the resistance of beneficial insects to viral pathogens.