Top Reads

In this Top Read, Morgan et al. (p. 1376) used RNA sequencing to investigate how TGF-β affects the development and function of invariant NKT (iNKT) cells. Thymic iNKT cells expressed genes associated with TGF-β signaling, whereas liver iNKT cells were enriched for genes associated with the IL-6–JAK–STAT pathway, mTORC1, and fatty acid metabolism. iNKT cells from animals with a thymocyte-specific TGF-β knockout displayed a decrease in adhesion molecules, including cadherin, CD103, and CD49α, suggesting that TGF-β is necessary for thymic iNKT cell development. In the liver, TGF-β was necessary for optimal CD49α expression along with IFN-γ and IL-4 production following iNKT cell stimulation. Together, these data show that whereas TGF-β signaling is important for iNKT cells postselection, there is heterogeneity in the role of TGF-β in thymic versus liver iNKT cells.

Clement et al. (p. 1348) demonstrated, in this Top Read, that the lysosomal-specific calcium channel, transient receptor potential cation channel, mucolipin subfamily, member 1 (TRPML1) mediated NK cell fitness. Genetic ablation of TRPML1 in human NK cell lines resulted in a lack of calcium flux when these NK cells were stimulated with TRPML1 agonists. The calcium overload led to lost membrane potential, increased reactive oxygen species stress, and decreased ATP production, suggesting that ablation of TRPML1 is sufficient to produce mitochondrial dysfunction. Phosphorylation of AMPK and an increase in autophagy marker LC3-II were observed following the activation of TRPML1 in wild-type NK cells. TRPML1 knockout NK cells also showed a decreased ability for chemotaxis. NK cells treated with a TRPML1 antagonist had reduced production of IFN and TNF. These data illuminate mechanisms of organelle cross-talk between lysosomal calcium and mitochondrial fitness.

In this Top Read, New et al. (p. 1320) elucidate the mechanism by which neonatal exposure to Streptococcus pyogenes (group A Streptococcus [GAS]) can delay type 1 diabetes (T1D). GAS induced the delay of T1D in neonatal, but not adult, NOD mice. Carbohydrates from the cell wall of GAS stimulated the expansion of N-acetyl-d-glucosamine (GlcNAc)-specific B-1b B cells, which migrated to the pancreas. These B-1b B cells produced IgM that bound to apoptotic β cells, activating the classical complement pathway, and increasing the efficiency of apoptotic β cell clearance. Although passive administration of polyclonal or monoclonal anti-GlcNAc Abs was unable to delay T1D, the adoptive transfer of the GlcNAc-specific B-1b B cells from GAS-immunized mice significantly reduced the incidence of T1D. These data demonstrate how environmental exposures early in life may alter the trajectory of autoimmune diseases.

Although RANKL is the main osteoclastogenic cytokine, TNF contributes to inflammation and bone erosion in rheumatoid arthritis and periodontal disease. In this Top Read, Ng et al. (p. 1340) show that TNF limits the differentiation of macrophages into osteoclasts through the induction of the Notch ligand, Jagged1. The TNF-dependent induction of Jagged1 in macrophages was shown to be dependent on the transcription factor RBP-J. Macrophages lacking Jagged1 can differentiate into osteoclasts in response to TNF stimulation. Concurrently, the overexpression of Jagged1 suppressed TNF-mediate osteoclastogenesis without altering the expression of TNF-induced inflammatory genes, indicating an osteoclast-specific function of Jagged1. Moreover, recombinant Jagged1 was able to suppress osteoclastogenesis in human macrophages. Based on these data, Jagged1 may be a potential therapeutic target to treat inflammatory bone diseases.