83 research outputs found
Invariant Natural Killer T Cell SubsetsβMore Than Just Developmental Intermediates
Invariant natural killer T (iNKT) cells are a CD1d-restricted T cell population that can respond to lipid antigenic stimulation within minutes by secreting a wide variety of cytokines. This broad functional scope has placed iNKT cells at the frontlines of many kinds of immune responses. Although the diverse functional capacities of iNKT cells have long been acknowledged, only recently have distinct iNKT cell subsets, each with a marked functional predisposition, been appreciated. Furthermore, the subsets can frequently occupy distinct niches in different tissues and sometimes establish long-term tissue residency where they can impact homeostasis and respond quickly when they sense perturbations. In this review, we discuss the developmental origins of the iNKT cell subsets, their localization patterns, and detail what is known about how different subsets specifically influence their surroundings in conditions of steady and diseased states
Overexpression of Interleukin (IL)-7 Leads to IL-15βindependent Generation of Memory Phenotype CD8+ T Cells
Transgenic (TG) mice expressing a high copy number of interleukin (IL)-7 cDNA under the control of the major histocomaptability complex (MHC) class II promoter display a 10β20-fold increase in total T cell numbers. Here, we show that the increase in T cell numbers in IL-7 TG mice is most apparent at the level of memory phenotype CD44hi CD122hi CD8+ cells. Based on studies with T cell receptor (TCR) TG mice crossed to IL-7 TG mice, increased levels of IL-7 may provide costimulation for TCR recognition of self-MHC ligands and thus cause naive CD8+ cells to proliferate and differentiate into memory phenotype cells. In addition, a marked increase in CD44hi CD122hi CD8+ cells was found in IL-7 TG IL-15β mice. Since these cell are rare in normal IL-15β mice, the dependency of memory phenotype CD8+ cells on IL-15 can be overcome by overexpression of IL-7
Constitutive Cytokine mRNAs Mark Natural Killer (NK) and NK T Cells Poised for Rapid Effector Function
Natural killer (NK) and NK T cells are tissue lymphocytes that secrete cytokines rapidly upon stimulation. Here, we show that these cells maintain distinct patterns of constitutive cytokine mRNAs. Unlike conventional T cells, NK T cells activate interleukin (IL)-4 and interferon (IFN)-Ξ³ transcription during thymic development and populate the periphery with both cytokine loci previously modified by histone acetylation. Similarly, NK cells transcribe and modify the IFN-Ξ³ gene, but not IL-4, during developmental maturation in the bone marrow. Lineage-specific patterns of cytokine transcripts predate infection and suggest evolutionary selection for invariant but distinct types of effector responses among the earliest responding lymphocytes
A minimal binding footprint on CD1d-glycolipid is a basis for selection of the unique human NKT TCR
Although it has been established how CD1 binds a variety of lipid antigens (Ag), data are only now emerging that show how Ξ±Ξ² T cell receptors (TCRs) interact with CD1-Ag. Using the structure of the human semiinvariant NKT TCRβCD1dβΞ±-galactosylceramide (Ξ±-GalCer) complex as a guide, we undertook an alanine scanning mutagenesis approach to define the energetic basis of this interaction between the NKT TCR and CD1d. Moreover, we explored how analogues of Ξ±-GalCer affected this interaction. The data revealed that an identical energetic footprint underpinned the human and mouse NKT TCRβCD1dβΞ±-GalCer cross-reactivity. Some, but not all, of the contact residues within the JΞ±18-encoded invariant CDR3Ξ± loop and VΞ²11-encoded CDR2Ξ² loop were critical for recognizing CD1d. The residues within the VΞ±24-encoded CDR1Ξ± and CDR3Ξ± loops that contacted the glycolipid Ag played a smaller energetic role compared with the NKT TCR residues that contacted CD1d. Collectively, our data reveal that the region distant to the protruding Ag and directly above the Fβ² pocket of CD1d was the principal factor in the interaction with the NKT TCR. Accordingly, although the structural footprint at the NKT TCRβCD1dβΞ±-GalCer is small, the energetic footprint is smaller still, and reveals the minimal requirements for CD1d restriction
CD1d-expressing Dendritic Cells but Not Thymic Epithelial Cells Can Mediate Negative Selection of NKT Cells
Natural killer T (NKT) cells are a unique immunoregulatory T cell population that is positively selected by CD1d-expressing thymocytes. Previous studies have shown that NKT cells exhibit autoreactivity, which raises the question of whether they are subject to negative selection. Here, we report that the addition of agonist glycolipid Ξ±-galactosylceramide (Ξ±-GalCer) to a fetal thymic organ culture (FTOC) induces a dose-dependent disappearance of NKT cells, suggesting that NKT cells are susceptible to negative selection. Overexpression of CD1d in transgenic (Tg) mice results in reduced numbers of NKT cells, and the residual NKT cells in CD1d-Tg mice exhibit both an altered VΞ² usage and a reduced sensitivity to antigen. Furthermore, bone marrow (BM) chimeras between Tg and WT mice reveal that CD1d-expressing BM-derived dendritic cells, but not thymic epithelial cells, mediate the efficient negative selection of NKT cells. Thus, our data suggest that NKT cells developmentally undergo negative selection when engaged by high-avidity antigen or abundant self-antigen
Differing roles of CD1d2 and CD1d1 proteins in type I natural killer T cell development and function
MHC class I-like CD1 molecules have evolved to present lipid-based antigens to T cells. Differences in the antigen-binding clefts of the CD1 family members determine the conformation and size of the lipids that are presented, although the factors that shape CD1 diversity remain unclear. In mice, two homologous genes, CD1D1 and CD1D2, encode the CD1d protein, which is essential to the development and function of natural killer T (NKT) cells. However, it remains unclear whether both CD1d isoforms are equivalent in their antigen presentation capacity and functions. Here, we report that CD1d2 molecules are expressed in the thymus of some mouse strains, where they select functional type I NKT cells. Intriguingly, the T cell antigen receptor repertoire and phenotype of CD1d2-selected type I NKT cells in CD1D1β/β mice differed from CD1d1-selected type I NKT cells. The structures of CD1d2 in complex with endogenous lipids and a truncated acyl-chain analog of Ξ±-galactosylceramide revealed that its Aβ²-pocket was restricted in size compared with CD1d1. Accordingly, CD1d2 molecules could not present glycolipid antigens with long acyl chains efficiently, favoring the presentation of short acyl chain antigens. These results indicate that the two CD1d molecules present different sets of self-antigen(s) in the mouse thymus, thereby impacting the development of invariant NKT cells
- β¦