Albert Bendelac

Role of NK1.1+ T Cells in a TH2 Response and in Immunoglobulin E Production

Immune responses dominated by interleukin-4 (IL-4)-producing T helper type 2 (TH2) cells or by interferon γ (IFN-γ)-producing T helper type 1 (TH1) cells express distinctive protection against infection with different pathogens. Interleukin-4 promotes the differentiation of naïve CD4+ T cells into IL-4 producers and suppresses their development into IFN-γ producers. CD1-specific splenic CD4+NK1.1+ T cells, a numerically minor population, produced IL-4 promptly on in vivo stimulation. This T cell population was essential for the induction of IL-4-producing cells and for switching to immunoglobulin E, an IL-4-dependent event, in response to injection of antibodies to immunoglobulin D.

Autoreactivity by design: innate B and T lymphocytes

Innate B and T lymphocytes are a subset of lymphocytes that express a restricted set of semi-invariant, germ-line-encoded, autoreactive antigen receptors. Although they have long been set apart from mainstream immunological thought, they now seem to represent a distinct immune-recognition strategy that targets conserved stress-induced self-structures, rather than variable foreign antigens. Innate lymphocytes regulate a range of infectious, tumour and autoimmune conditions. New studies have shed light on the principles and mechanisms that drive their unique development and function, and show their resemblance to another subset of innate lymphocytes, the natural killer cells.

Mouse NK1+ T cells

Mouse NK1+ T cells constitute a special subset of alpha beta TCR+ T cells that express natural killer surface receptors and are thought to play an immunoregulatory role because of their unique ability to secrete IL-4 within minutes of primary activation. The recent discovery that they recognize non-polymorphic MHC class I like ligands encoded by CD1 family genes sheds a new light on unusual aspects of their development as well as on some of the possible ways in which they might influence the regulation of the T-helper cell (types 1 and 2) classes of immune responses.

CD1d Endosomal Trafficking Is Independently Regulated by an Intrinsic CD1d-Encoded Tyrosine Motif and by the Invariant Chain

Endosomal trafficking is an essential component of the CD1 pathway of lipid antigen presentation to T cells. We demonstrate that CD1d access to endosomal compartments is under dual regulation by an intrinsic tyrosine-based motif, which governs intense recycling between the plasma membrane and the endosome, and by the invariant chain, with which CD1d associates in the endoplasmic reticulum. Both pathways independently enhance antigen presentation to V(alpha)14(+) NKT cells, the main subset of CD1d-restricted T cells. These results reveal the complexity of CD1d trafficking and suggest that the invariant chain was a component of ancestral antigen presentation pathways prior to the evolution of MHC and CD1.

Multiple defects in antigen presentation and T cell development by mice expressing cytoplasmic tail–truncated CD1d

For members of the CD1 family of β2-microglobulin–associated lipid-presenting molecules, tyrosine-based motifs in the cytoplasmic tail and invariant chain (Ii) govern glycoprotein trafficking through endosomal compartments. Little is known about the intracellular pathways of CD1 trafficking and antigen presentation. However, in vitro studies with cells transfected with mutant CD1 that had a truncated cytoplasmic tail have suggested a role for these tyrosine motifs in some, but not all, antigenic systems. By introducing a deletion of the tyrosine motif into the germ line, and through homologous recombination in embryonic stem cells, we now describe knock-in mice with the CD1d cytoplasmic tail deleted. Despite adequate surface CD1d expression and the presence of Ii, these mutant mice showed multiple and selective abnormalities in intracellular trafficking, antigen presentation and T cell development, demonstrating the critical functions of the CD1d cytoplasmic tail motif in vivo.

Adjuvants of immunity: Harnessing innate immunity to promote adaptive immunity

Since Jules Freund reported that crude mycobacterial extracts greatly promoted immune responses to antigens ([1][1]), the use of adjuvants has become a widespread, but poorly understood practice to promote T and B cell responses ([2][2]). Recent studies have begun to identify the chemical nature of

Cutting edge: the IgG response to the circumsporozoite protein is MHC class II-dependent and CD1d-independent: exploring the role of GPIs in NK T cell activation and antimalarial responses.

Biochemical analysis has suggested that self GPI anchors are the main natural ligand associated with mouse CD1d molecules. A recent study reported that Vα14+ NK T cells responded to self as well as foreign (parasite-derived) GPIs in a CD1d-dependent manner. It further reported that the IgG response to the Plasmodium berghei malarial circumsporozoite (CS) protein was severely impaired in CD1d-deficient mice, leading to a model whereby NK T cells, upon recognition of CD1d molecules presenting the CS-derived GPI anchor, provide help for B cells secreting anti-CS Abs. We tested this model by comparing the anti-CS Ab responses of wild-type, CD1d-deficient, and MHC class II-deficient mice. We found that the IgG response to the CS protein was solely MHC class II-dependent. Furthermore, by measuring the response of a broad panel of CD1d-autoreactive T cells to GPI-deficient CD1d-expressing cells, we found that GPIs were not required for autoreactive responses.

CD1-restricted T-cell responses and microbial infection

CD1, a conserved family of major histocompatibility (MHC)-like glycoproteins in mammals, specializes in capturing lipid rather than peptide antigen for presentation to T lymphocytes. The principles and mechanisms of this newly discovered immune strategy differ markedly from those governing classical MHC–peptide presentation. They might be exploited for the design of new lipid-based microbial vaccines and adjuvants.

Thymocyte expression of cathepsin L is essential for NKT cell development

CD1d antigen presentation to natural killer T (NKT) cells expressing the semi-invariant T cell receptor Vα14Jα18 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 Vα14+NK1.1+ T cells. In addition, catL expression in thymocytes is critical not only for selection of these cells in vivo but also for stimulation of Vα14+NK1.1+ 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 Vα14+NK1.1+ 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.

Unaltered phenotype, tissue distribution and function of Vα14+ NKT cells in germ‐free mice

The expression pattern of mouse CD1d and the tissue distribution of CD1d‐restricted Vα14‐Jα281 NKT cells suggest that the liver and the marginal zone of the spleen might be preferred sites of activation of this potent innate pathway of early cytokine secretion. Because these tissues are particularly involved with the filtration of blood‐borne pathogens, and because NKT cells with an activatedu2009/u2009memory phenotype accumulate over the first weeks of life and their CD1 ligands bind microbial glycolipids, it has been hypothesized that expansion of the NKT cell subset may be driven by exposure to the microbial environment. To test this hypothesis, we analyzed the frequency, surface phenotype and functional properties of NKT cells in normal and in germ‐free C57BLu2009/u20096 mice. Surprisingly, we found that the NKT cell subset develops in the presence or absence of a microbial environment. Although these results do not rule out the possibility that NKT cells exert a protective function against some microbial agents, they demonstrate that non microbial ligands, possibly self‐antigens are sufficient for the generation, maturation and peripheral accumulation of NKT cells.