A Distinctive Cytoplasmic Tail Contributes to Low Surface Expression and Intracellular Retention of the Patr-AL MHC Class I Molecule.

Chimpanzees have orthologs of the six fixed, functional human MHC class I genes. But, in addition, the chimpanzee has a seventh functional gene, Patr-AL, which is not polymorphic but contributes substantially to population diversity by its presence on only 50% of MHC haplotypes. The ancestral AL gene emerged long before the separation of human and chimpanzee ancestors and then subsequently and specifically lost function during human evolution, but was maintained in chimpanzees.

PLZF Controls the Expression of a Limited Number of Genes Essential for NKT Cell Function.

Natural killer (NKT) T cells exhibit tissue distribution, surface phenotype, and functional responses that are strikingly different from those of conventional T cells. The transcription factor PLZF is responsible for most of these properties, as its ectopic expression in conventional T cells is sufficient to confer to them an NKT-like phenotype. The molecular program downstream of PLZF, however, is largely unexplored.

β-Selection-induced proliferation is required for αβ T cell differentiation.

Proliferation and differentiation are tightly coordinated to produce an appropriate number of differentiated cells and often exhibit an antagonistic relationship. Developing T cells, which arise in the thymus from a minute number of bone-marrow-derived progenitors, undergo a major expansion upon pre-T cell receptor (TCR) expression. The burst of proliferation coincides with differentiation toward the αβ T cell lineage-but the two processes were previously thought to be independent from one another, although both were driven by signaling from pre-TCR and Notch receptors.

Although divergent in residues of the peptide binding site, conserved chimpanzee Patr-AL and polymorphic human HLA-A*02 have overlapping peptide-binding repertoires.

Patr-AL is an expressed, non-polymorphic MHC class I gene carried by ∼50% of chimpanzee MHC haplotypes. Comparing Patr-AL(+) and Patr-AL(-) haplotypes showed Patr-AL defines a unique 125-kb genomic block flanked by blocks containing classical Patr-A and pseudogene Patr-H. Orthologous to Patr-AL are polymorphic orangutan Popy-A and the 5' part of human pseudogene HLA-Y, carried by ∼10% of HLA haplotypes.

αβ versus γδ fate choice: counting the T-cell lineages at the branch point.

Both αβ and γδ T cells develop in the thymus from a common progenitor. Historically distinguished by their T-cell receptor (TCR), these lineages are now defined on the basis of distinct molecular programs. Intriguingly, in many transgenic and knockout systems these programs are mismatched with the TCR type, leading to the development of γδ lineage cells driven by αβTCR and vice versa.

Thymocyte selection: chemokine signaling is not only about the destination.

The development and function of lymphocytes depend upon their precise migration in response to chemoattractant cytokines, or chemokines. Two recent reports suggest that, during thymic beta-selection, the binding of the chemokine CXCL12 to the receptor CXCR4 on thymocytes provides not only directional but also developmental cues.

Alphabeta versus gammadelta lineage choice at the first TCR-controlled checkpoint.

Alphabeta and gammadelta T cells develop in the thymus from a common precursor. Although lineages initially were defined by the type of TCR they express, it soon became clear that the TCR type per se does not play a deterministic role in the lineage decision, since in various transgenic and knockout models, as well as in a small fraction of cells in wt mice, the TCRgammadelta can drive the differentiation of alphabeta lineage cells and the TCRalphabeta can drive differentiation of gammadelta lineage cells. Thus until recently it was unclear what determines lineage choice and at which stage the two lineages diverge.

KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C.

Human killer cell immunoglobulin-like receptors (KIRs) are distinguished by expansion of activating KIR2DS, whose ligands and functions remain poorly understood. The oldest, most prevalent KIR2DS is KIR2DS4, which is represented by a variable balance between "full-length" and "deleted" forms. We find that full-length 2DS4 is a human histocompatibility leukocyte antigen (HLA) class I receptor that binds specifically to subsets of C1+ and C2+ HLA-C and to HLA-A*11, whereas deleted 2DS4 is nonfunctional.

Synergistic polymorphism at two positions distal to the ligand-binding site makes KIR2DL2 a stronger receptor for HLA-C than KIR2DL3.

Interactions between HLA-C ligands and inhibitory killer cell Ig-like receptors (KIR) control the development and response of human NK cells. This regulatory mechanism is usually described by mutually exclusive interactions of KIR2DL1 with C2 having lysine 80, and KIR2DL2/3 with C1 having asparagine 80. Consistent with this simple rule, we found from functional analysis and binding assays to 93 HLA-A, HLA-B, and HLA-C isoforms that KIR2DL1*003 bound all C2, and only C2, allotypes.

Unusual selection on the KIR3DL1/S1 natural killer cell receptor in Africans.

Interactions of killer cell immunoglobulin-like receptors (KIRs) with major histocompatibility complex (MHC) class I ligands diversify natural killer cell responses to infection. By analyzing sequence variation in diverse human populations, we show that the KIR3DL1/S1 locus encodes two lineages of polymorphic inhibitory KIR3DL1 allotypes that recognize Bw4 epitopes of protein">HLA-A and HLA-B and one lineage of conserved activating KIR3DS1 allotypes, also implicated in Bw4 recognition. Balancing selection has maintained these three lineages for over 3 million years.

Single-cell analysis of the human NK cell response to missing self and its inhibition by HLA class I.

Natural killer (NK) cells activate quickly in response to pathogens, tumors, and allogeneic hematopoietic cell transplants. Modulating the NK cell response are clonally distributed NK cell receptors that survey cells for change in the expression of major histocompatibility complex (MHC) class I and structurally related ligands. Here the enzyme-linked immunospot (ELISPOT) assay, intracellular cytokine staining (ICS), and short-term culture were used to quantify the response of bulk NK cell populations from human donors to HLA class I-deficient 221 cells and to 221 cells transfected with single HLA class I allotypes.

The protein made from a common allele of KIR3DL1 (3DL1*004) is poorly expressed at cell surfaces due to substitution at positions 86 in Ig domain 0 and 182 in Ig domain 1.

KIR3DL1 is an inhibitory HLA-B receptor of human NK and T cells that exhibits genetic and phenotypic polymorphism. KIR3DL1*004, a common allotype, cannot be detected on the surface of PBLs using the KIR3DL1-specific Ab DX9. The nature of this phenotype was investigated through comparison of 3DL1*004 with 3DL1*002, an allele giving high DX9 binding to cell surfaces.

Stress management: MHC class I and class I-like molecules as reporters of cellular stress.

The evolutionarily ancient intracellular stress response protects cells from the effects of external and internal forces which perturb cellular metabolism. Members of the major histocompatibility complex (MHC) class I-like superfamily act as cell surface indicators of the intracellular stress response. Cellular immunity employs these indicators as a cue for elimination of damaged, infected, and malignant cells, promoting the health of the individual and the evolutionary success of the species.

Continuous T cell receptor signaling required for synapse maintenance and full effector potential.

Although signals through the T cell receptor (TCR) are essential for the initiation of T helper cell activation, it is unclear what function such signals have during the prolonged T cell-antigen-presenting cell contact. Here we simultaneously tracked TCR-CD3 complex and phosphoinositide 3-kinase activity in single T cells using three-dimensional video microscopy. Despite rapid internalization of most of the TCR-CD3, TCR-dependent signaling was still evident up to 10 h after conjugate formation.

Identification of a germ-line pro-B cell subset that distinguishes the fetal/neonatal from the adult B cell development pathway.

Studies presented here show that the expression of CD4, MHC class II (Ia,) and B220 cleanly resolves a major and a minor subset within the earliest pro-B cell population (germ-line pro-B) in adult bone marrow (BM). The major subset expresses intermediate B220 and low CD4 levels. The minor subset, which constitutes roughly 20% of the adult germ-line pro-B, expresses very low B220 levels and does not express CD4.