Improved Outcomes in NOD Mice Treated with a Novel Th2 Cytokine-Biasing NKT Cell Activator

Abstract

Activation of CD1d-restricted invariant NKT (iNKT) cells by α-galactosylceramide (αGalCer) significantly suppresses development of diabetes in NOD mice. The mechanisms of this protective effect are complex, involving both Th1 and Th2 cytokines and a network of regulatory cells including tolerogenic dendritic cells. In the current study, we evaluated a newly described synthetic αGalCer analog (C20:2) that elicits a Th2-biased cytokine response for its impact on disease progression and immunopathology in NOD mice. Treatment of NOD mice with αGalCer C20:2 significantly delayed and reduced the incidence of diabetes. This was associated with significant suppression of the late progression of insulitis, reduced infiltration of islets by autoreactive CD8+ T cells, and prevention of progressive disease-related changes in relative proportions of different subsets of dendritic cells in the draining pancreatic lymph nodes. Multiple favorable effects observed with αGalCer C20:2 were significantly more pronounced than those seen in direct comparisons with a closely related analog of αGalCer that stimulated a more mixed pattern of Th1 and Th2 cytokine secretion. Unlike a previously reported Th2-skewing murine iNKT cell agonist, the αGalCer C20:2 analog was strongly stimulatory for human iNKT cells and thus warrants further examination as a potential immunomodulatory agent for human disease.

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

“…A similar protection was observed after specific iNKT cell stimulation with exogenous ligands, a-galactosylceramide (a-GalCer) and its analogues [8][9][10][11]. Early reports suggested that iNKT cell protection was associated with the induction of a Th2 response to islet autoantigens [8,[10][11][12]. However, following studies using the transfer of anti-islet T cells showed that iNKT cells inhibit the differentiation of these auto-reactive T cells into effector cells during their priming in pancreatic lymph nodes (PLNs) [13,14].…”

“…iNKT cells are reduced in number in diabetes-prone NOD mice [4,5], and increasing the number of iNKT cells by adoptive transfer [6,7] or via the introduction of a Va14-Ja18 transgene, reduces significantly the progression of the disease [6]. A similar protection was observed after specific iNKT cell stimulation with exogenous ligands, a-galactosylceramide (a-GalCer) and its analogues [8][9][10][11]. Early reports suggested that iNKT cell protection was associated with the induction of a Th2 response to islet autoantigens [8,[10][11][12].…”

Mouse and human iNKT cell agonist β-mannosylceramide reveals a distinct mechanism of tumor immunity

“…Schmieg et al observed that the C-glycoside analog of α-GalCer (α-C-GalCer) induced an immune response more skewed toward Th1 (IFN-γ) cytokines and was even more effective against B16 melanoma metastasis, further supporting the widely held belief that IFN-γ induction is a key factor for generating antitumor immunity (18). Other studies have characterized the functional activity of analogs of α-GalCer that induce more Th2 cytokine production, such as C20:2 and OCH (15,16,21,22).…”

Invariant NKT Cells in Hyperplastic Skin Induce a Local Immune Suppressive Environment by IFN-γ Production

“…Factors regulating this polarization of iNKT cells may include, but are not exclusive to, strength of TCR signal (33,34), costimulation (35), or functionally distinct iNKT subsets (36,37). Activating stimuli-inducing IFN-g and other Th1 cytokine production by iNKT cells generally leads to infection clearance and antitumor activity (38)(39)(40).…”