Invariant NKT Cell Activation Is Potentiated by Homotypic trans-Ly108 Interactions

Abstract

Invariant NKT (iNKT) cells are innate lymphocytes that respond to glycolipids presented by the MHC class Ib molecule CD1d and are rapidly activated to produce large quantities of cytokines and chemokines. iNKT cell development uniquely depends on interactions between double-positive thymocytes that provide key homotypic interactions between signaling lymphocyte activation molecule (SLAM) family members. However, the role of SLAM receptors in the differentiation of iNKT cell effector subsets and activation has not been explored. In this article, we show that C57BL/6 mice containing the New Zealand Black locus have profound alterations in Ly108, CD150, and Ly9 expression that is associated with iNKT cell hyporesponsiveness. This loss of function was only apparent when dendritic cells and iNKT cells had a loss of SLAM receptor expression. Using small interfering RNA knockdowns and peptide-blocking strategies, we demonstrated that-Ly108 interactions between dendritic cells and iNKT cells are critical for robust activation. LY108 costimulation similarly increased human iNKT cell activation. Thus, in addition to its established role in iNKT cell ontogeny, Ly108 regulates iNKT cell function in mice and humans.

TCR signal strength controls thymic differentiation of iNKT cell subsets

“…In these conditions, we do not detect PLZF expression at any time point post stimulation. As reported previously 17 , 18 , co-stimulation with the SLAM family member Ly108 increases the proportion of cells expressing Egr2 as well as the level of expression per cell. Interestingly, cells expressing the highest levels of Egr2 begin to express the PLZF protein around 32 h post stimulation with the proportion of PLZF + cells increasing as a function of time.…”

“…The TCR signals received by iNKT cell precursors during selection are associated with high expression of the Ras- 14 and Ca 2+ -dependent transcription factors Egr1 and, especially, Egr2 15 , 16 . Interestingly, high expression levels of Egr2 in pre-selection DP thymocytes are potentiated by co-stimulation through Ly108 17 , 18 . Egr2 directly regulates the expression of several genes involved in the development of iNKT cells, including PLZF and CD122, one of the chains of the IL-15 receptor 15 .…”

Impaired B cell anergy is not sufficient to breach tolerance to nuclear antigen in Vκ8/3H9 lupus-prone mice

“…Here we show that this defect extends to ssDNA-reactive B cells in NZB c1 dKI mice, suggesting that the genetic polymorphism(s) in the c1 region leading to these intrinsic B cell defects act on B cells with a range of antigen affinities and specificities. It is well established that members of the SLAM family, particularly Ly108, are the primary candidate genes in the c1(96-100) interval [40,41], and there is evidence that Ly108 may alter tolerance induction through direct effects on B cell function in addition to its role in mediating GC tolerance [42][43][44][45][46]. Since the NZB Ly108 allele has been shown to reduce the strength of BCR signalling and this plays an important role in anergy induction, it is probable that the NZB allelic variant leads to the impaired anergy induction and/or breach of anergy observed in these mouse strains.…”

Mixed Signals: Co-Stimulation in Invariant Natural Killer T Cell-Mediated Cancer Immunotherapy

“…To make these receptors as efficient as possible, it is worth exploring new possible co-stimulatory domains not traditionally included in CARs. A recent study conducted by Baglaenko et al found a new role for Ly108 in iNKT cells ( 109 ). Ly108 has been previously established to play a role in iNKT cell development; however, this recent study found that peripheral trans-Ly108 interactions between APCs and iNKT cells enhanced the ability of iNKT cells to secrete cytokines and that loss of Ly108 expression resulted in defective iNKT cell homeostasis in mice.…”