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NKT cells are innate-like T cells with powerful regulatory functions that are a promising target for immunotherapy. The efficacy of glycolipids, such as the prototypic NKT cell antagonist α-galactosylceramide (αGalCer), is currently being evaluated in clinical trials, but little is known about factors that target lipid antigens for CD1d presentation and NKT cell activation in vivo. Lipid uptake via the LDL receptor (LDLR) has been shown for digalactosylceramide; however, whether this pathway contributes to CD1d presentation of other important NKT cell agonists remains unclear. We therefore investigated receptor-mediated uptake pathways for CD1d presentation using a panel of structurally diverse lipid antigens. We found that uptake via scavenger receptors was essential for the CD1d presentation of αGalCer and Sphingomonas glycolipids. Moreover, in vivo NKT cell responses, i.e., cytokine production, proliferation, and NKT cell help for adaptive CD4+ and CD8+ T cells, required the uptake of αGalCer via scavenger receptor A. Importantly, our data indicate that structural characteristics of glycolipids determine their receptor binding and direct individual lipids toward different uptake pathways. These results reveal an important contribution of scavenger receptors in the selection of lipids for CD1d presentation and identify structural motifs that may prove useful for therapeutic NKT cell vaccination.

During the 2004 International Congress of Immunology in Montreal, a panel of experts gathered for an "Ideashop" discussion on the potential role of innate immunity in autoimmunity and the ways in which this might be targeted in future therapies.

A committed precursor to innate lymphoid cell lineages, but not classical natural killer and lymphoid tissue inducer cells, is derived from common lymphoid precursors and distinguished by high levels of expression of the transcription factor PLZF. Innate lymphoid cell precursors identified Knowledge of the developmental pathways and lineage relationships of the precursors to innate lymphocytes is important because these cells serve key protective functions in infection and homeostasis at mucosal barriers, and because of their crosstalk with epithelium and microbiota. This study identifies a committed common lymphoid-derived precursor to innate lymphoid cell (ILC) lineages. The progenitor cells, termed ILCPs (innate lymphoid cell precursors), are distinct from classical natural killer (NK) and lymphoid tissue inducer cells, thus demonstrating that similar functional programs arise independently in different lineages of innate lymphocytes. The findings also imply the presence of highly specialized innate lymphoid lineages within what was previously regarded as a broader NK-cell population. Innate lymphoid cells (ILCs) specialize in the rapid secretion of polarized sets of cytokines and chemokines to combat infection and promote tissue repair at mucosal barriers.sup.1,2,3,4,5,6,7,8,9. Their diversity and similarities with previously characterized natural killer (NK) cells and lymphoid tissue inducers (LTi) have prompted a provisional classification of all innate lymphocytes into groups 1, 2 and 3 solely on the basis of cytokine properties.sup.10, but their developmental pathways and lineage relationships remain elusive. Here we identify and characterize a novel subset of lymphoid precursors in mouse fetal liver and adult bone marrow that transiently express high amounts of PLZF, a transcription factor previously associated with NK T cell development.sup.11,12, by using lineage tracing and transfer studies. PLZF.sup.high cells were committed ILC progenitors with multiple ILC1, ILC2 and ILC3 potential at the clonal level. They excluded classical LTi and NK cells, but included a peculiar subset of NK1.1.sup.+DX5.sup.- 'NK-like' cells residing in the liver. Deletion of PLZF markedly altered the development of several ILC subsets, but not LTi or NK cells. PLZF.sup.high precursors also expressed high amounts of ID2 and GATA3, as well as TOX, a known regulator of PLZF-independent NK and LTi lineages.sup.13. These findings establish novel lineage relationships between ILC, NK and LTi cells, and identify the common precursor to ILCs, termed ILCP. They also reveal the broad, defining role of PLZF in the differentiation of innate lymphocytes., Author(s): Michael G. Constantinides [sup.1] , Benjamin D. McDonald [sup.1] , Philip A. Verhoef [sup.1] , Albert Bendelac [sup.1] Author Affiliations: (1) Department of Pathology, Committee on Immunology, The Howard [...]

The differentiation of several T- and B-cell effector programs in the immune system is directed by signature transcription factors that induce rapid epigenetic remodelling. Here we report that promyelocytic leukaemia [...]

The potent regulatory properties of NKT cells render this subset of lipid-specific T cells a promising target for immunotherapeutic interventions. The marine sponge glycolipid α]-galactosylceramide (αGalCer) is the prototypic NKT cell agonist, which elicits this function when bound to CD1d. However, our understanding of the in vivo properties of NKT cell agonists and the host factors that control their bioactivity remains very limited. In this report, we isolated the enzyme fatty acid amide hydrolase (FAAH) from mouse serum as an αGalCer-binding protein that modulates the induction of key effector functions of NKT cells in vivo. FAAH bound αGalCer in vivo and in vitro and was required for the efficient targeting of lipid antigens for CD1d presentation. Immunization of Faah-deficient mice with αGalCer resulted in a reduced systemic cytokine production, but enhanced expansion of splenic NKT cells. This distinct NKT response conferred a drastically increased adjuvant effect and strongly promoted protective CTL responses. Thus, our findings identify not only the presence of FAAH in normal mouse serum, but also its critical role in the tuning of immune responses to lipid antigens by orchestrating their transport and targeting for NKT cell activation. Our results suggest that the serum transport of lipid antigens directly shapes the quality of NKT cell responses, which could potentially be modulated in support of novel vaccination strategies., Introduction The NKT cell population represents a specialized subset of lipid antigen-specific T cells with important regulatory functions (1-3). NKT cells are characterized by the expression of an invariant Vα [...]

Some [gamma][delta] and [alpha][beta] T lymphocytes exhibit an 'innate' phenotype associated with rapid cytokine responses. The PLZF transcription factor is essential for the innate phenotype of NKT cells. This report shows that PLZF is likewise responsible for the innate, NKT-like phenotype of V[gamma]1+V[delta]6.3/V[delta]6.4+ cells. TCR cross-linking induced PLZF expression in all polyclonal immature [gamma][delta] thymocytes, suggesting that agonist selection might be required for PLZF induction. Transgenic expression of V[gamma]1V[delta]6.4 TCR was sufficient to support the development of large numbers of PLZF+ T cells, further supporting the importance of the TCR for PLZF induction. Interestingly, expression of this TCR transgene led to the development of spontaneous dermatitis. agonist selection | innate T cells | transgenes

Short or polyunsaturated lipid variants of the NKT cell antigen [alpha]-galactosylceramide ([alpha]GC) exhibit decreased potency and a Th2 bias in vivo despite conserved TCR contact residues and stable binding to CD1d at neutral and acidic pH. Using reagents to directly visualize lipids in their free or CD1d-bound form, we determined that, contrary to predictions, these lipids reached the lysosome better than [alpha]GC. However, in contrast with [alpha]GC, they loaded CD1d at the cell surface and underwent immediate pH-dependent dissociation upon recycling to the lysosome. In cell-free assays, ultrafast dissociation of preformed complexes could be induced at acidic pH only when free competitor lipids were added, suggesting active lipid displacement. These findings provide a common cell biological explanation for the decreased stimulatory properties of short and polyunsaturated [alpha]GC variants. They also suggest that direct lipid displacement is a potent mechanism underlying highly dynamic lipid exchange reactions in the lysosomal compartment that shape the repertoire of lipids associated with CD1d.

Author(s): Jochen Mattner [1]; Kristin L. DeBord [2]; Nahed Ismail [3]; Randal D. Goff [4]; Carlos Cantu, III [5]; Dapeng Zhou [1]; Pierre Saint-Mezard [1]; Vivien Wang [1]; Ying Gao [...]