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Short or polyunsaturated lipid variants of the NKT cell antigen a-galactosylceramide (sGC) 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 αGC. However, in contrast with αGC, they loaded CD1 d 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 αGC 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. [ABSTRACT FROM AUTHOR]

Upon reaching the mature heat stable antigen (HSA)low thymic developmental stage, CD1d-restricted Vα14-Jα18 thymocytes undergo a well-characterized sequence of expansion and differentiation steps that lead to the peripheral interleukin-4/interferon-γ-producing NKT phenotype. However, their more immature HSAhigh precursors have remained elusive, and it has been difficult to determine unambiguously whether NKT cells originate from a CD4+CD8+ double-positive (DP) stage, and when the CD4+ and CD4-CD8- double-negative (DN) NKT subsets are formed. Here, we have used a CD1d tetramer-based enrichment strategy to physically identify HSAhigh precursors in thymuses of newborn mice, including an elusive DPlow stage and a CD4+ stage, which were present at a frequency of ~10-6. These HSAhigh DP and CD4+ stages appeared to be nondividing, and already exhibited the same Vβ8 bias that characterizes mature NKT cells. This implied that the massive expansion of NKT cells is separated temporally from positive selection, but faithfully amplifies the selected TCR repertoire. Furthermore, we found that, unlike the DN γδ T cells, the DN NKT cells did not originate from a pTα-independent pathway bypassing the DP stage, but instead were produced during a short window of time from the conversion of a fraction of HSAlow NK1.1neg CD4 cells. These findings identify the HSAhigh CD4+ stage as a potential branchpoint between NKT and conventional T lineages and between the CD4 and DN NKT sublineages. [ABSTRACT FROM AUTHOR]

CD1d antigen presentation to natural killer T (NKT) cells expressing the semi-invariant T cell receptor V[sub α]14J[sub α]18 requires CD1d trafficking through endosomal compartments; however, the endosomal events remain undefined. We show that mice lacking the endosomal protease cathepsin L (catL) have greatly reduced numbers of V[sub α]14[sup +]NK1.1[sup +] T cells. In addition, catL expression in thymocytes is critical not only for selection of these cells in vivo but also for stimulation of V[sub α]14[sup +]NK1.1[sup +]T cells in vitro. CD1d cell-surface expression and intracellular localization appear normal in catL-deficient thymocytes, as does the lysosomal morphology; this implies a specific role for catL in regulating presentation of natural CD1d ligands mediating V[sub α]14[sup +]NK1.1[sup +]T cell selection. These data implicate lysosomal proteases as key regulators of not only classical major histocompatibility complex class II antigen presentation but also nonclassical CD1d presentation. [ABSTRACT FROM AUTHOR]

Discusses the CD1 immune strategy, that of a conserved family of major histocompatibility (MHC)-like glycoproteins. How these proteins focus on capturing lipid rather than peptide antigen for presentation to T lymphocytes; Implications for the development of novel, lipid-based adjuvant and vaccines.

Reports on the finding that in mice, an entire subset of alpha-beta thymocytes with a unique phenotype was found to be CD1-specific. Evidence that CD1 has a general role in selecting and interacting with specialized alpha-beta T cells.

Focuses on the mechanism of lipid antigen presentation by CD 1 molecules and antigen-presenting cells. Properties of CD 1 molecules; Manipulation of lipid antigen glucomonomycolates (GMM) and CD1b molecules; Role of GMM length on lipid presentation.

Analyzes the role of CD1d-restricted autoreactive natural killer (NK) T cells in various disease conditions. Developmental branchpoints of NK T cells; Influence of an inhibitory NK receptors on the autoreactivity of NK T cells; Occurrence of a major lineage expansion in the thymus.