Type II NKT-TFH cells against Gaucher lipids regulate B-cell immunity and inflammation

Abstract

Key Points• A new subset of human and murine type II NKT-T FH cells against Gaucher lipids that regulate B-cell immunity.• A novel pathway for B-cell help providing a mechanism underlying chronic B-cell activation and gammopathy in metabolic lipid disorders.Chronic inflammation including B-cell activation is commonly observed in both inherited (Gaucher disease [GD]) and acquired disorders of lipid metabolism. However, the cellular mechanisms underlying B-cell activation in these settings remain to be elucidated. Here, we report that b-glucosylceramide 22:0 (bGL1-22) and glucosylsphingosine (LGL1), 2 major sphingolipids accumulated in GD, can be recognized by a distinct subset of CD1d-restricted human and murine type II natural killer T (NKT) cells. Human bGL1-22-and LGL1-reactive CD1d tetramer-positive T cells have a distinct T-cell receptor usage and genomic and cytokine profiles compared with the classical type I NKT cells. In contrast to type I NKT cells, bGL1-22-and LGL1-specific NKT cells constitutively express T-follicular helper (T FH ) phenotype. Injection of these lipids leads to an increase in respective lipidspecific type II NKT cells in vivo and downstream induction of germinal center B cells, hypergammaglobulinemia, and production of antilipid antibodies. Human bGL1-22-and LGL1-specific NKT cells can provide efficient cognate help to B cells in vitro. Frequency of LGL1-specific T cells in GD mouse models and patients correlates with disease activity and therapeutic response. Our studies identify a novel type II NKT-mediated pathway for glucosphingolipid-mediated dysregulation of humoral immunity and increased risk of B-cell malignancy observed in metabolic lipid disorders. (Blood. 2015;125(8):1256-1271

ABC transporters and NR4A1 identify a quiescent subset of tissue-resident memory T cells

“…Spleen was harvested, and single-cell suspensions were made and stained for FACS to detect human T cell engraftment. , and the diversity of TCR was profiled using high-throughput sequencing of rearranged TCR β loci from genomic DNA by Adaptive Biotechnologies as previously described (43).…”

CD1b-autoreactive T cells recognize phospholipid antigens and contribute to antitumor immunity against a CD1b+T cell lymphoma

“…Unlike both types of CD1d-restricted NKT cells, which are activated by b-linked glycosphingolipids, HJ1 T cells were not activated by sphingolipids. 22,[41][42][43] A recent study also suggests that mammalian a-linked glycosphingolipids can activate type I NKT cells. 44 Although ether-linked forms of pLPE and lysophaphatidic have been implicated in the selection of type I NKT cells, nothing is known about the selecting self-lipids for type II NKT cells and group 1 CD1-reactive T cells.…”

B Cell Help by CD1d-Rectricted NKT Cells

“…This lipid accumulation leads to chronic inflammation and B-cell activation, often resulting in monoclonal and polyclonal gammopathy [77]. βGL1 and LGL1 loaded CD1d tetramers clearly demonstrate the existence of lipid specific CD1d-restricted NKT cells displaying type II characteristics, in terms of diverse TCR expression, and different genomic and cytokine profile compared to type I NKT cells [78]. Interestingly, the primary type II NKT cells found in GD patients exhibit a constitutive TFH phenotype.…”