Autophagy is dispensable for B-cell development but essential for humoral autoimmune responses

Abstract

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...

Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease

“…+ and CD8 + memory T cells, each of which exhibits an intrinsic requirement for autophagy for their survival (39)(40)(41)(42). We further demonstrate that TIGIT + Tregs coexpress CXCR4, a chemokine receptor that facilitates migration to, and retention in, the BM, where stromal cells express high levels of SDF-1 (43), thus explaining the preferential enrichment of TIGIT + Tregs at this site.…”

Mechanistic roles of autophagy in hematopoietic differentiation

“…Importantly, in both these chimeric models, HSCs lack autophagy, and the earliest stem and progenitor cells have been shown to critically require autophagy for their own maintenance and differentiation, potentially exacerbating the observed B-cell phenotype [25]. Indeed, in a recent study using Mb1-cre-, CD19-cre-, or CD21-cremediated excision of Atg5 at different stages after the pro-B-cell stage suggests that autophagy is dispensable for development after the pro-B-cell stage [62]. It is intriguing to speculate that deletion of Atg genes at an early stem/progenitor stage may have led to cell extrinsic homeostatic feedback, or allowed enough time for metabolic/signaling changes within the cell to develop.…”

The PI3K pathway in B cell metabolism

“…Although no impact on early B cell development was observed in these mice, mature B cell numbers were slightly, but significantly reduced. A similar decrease in mature B cell numbers was observed if Atg5 is deleted at the transitional B cell stage using CD21-cre, suggesting that Atg5 is needed for B cell maturation and/or survival in the periphery (Arnold et al, 2015). Discrepancies observed in these two mouse models could possibly be attributed to the different developmental stages of Atg5 deletion.…”

“…In the B cell lineage, autophagy has been shown to play an important role in the maintenance of plasma cells (Pengo et al, 2013, Conway et al, 2013) and memory B cells (Chen et al, 2015, Chen et al, 2014). Deletion of Atg5, which is essential for the formation of the autophagosome, results in a dramatic reduction in B1 cell numbers (Miller et al, 2008, Arnold et al, 2015). However the role of autophagy in conventional B cell development and maintenance remains controversial.…”