Abstract Background Pathogenic or regulatory effects of natural killer (NK) cells are implicated in many autoimmune diseases, but evidence multiple sclerosis (MS) and its murine models remains equivocal. In an effort to illuminate this, we have here analysed expression the prototypic NK cell marker, NCR1 (natural cytotoxicity triggering receptor; NKp46; CD335), activating receptor expressed by virtually all therefore considered a pan-marker for cells. The only definitive ligand is influenza...

Complete cancer regression occurs in a subset of patients following adoptive T cell therapy (ACT) ex vivo expanded tumor-infiltrating lymphocytes (TILs). However, the low success rate presents great challenge to broader clinical application. To provide insight into TIL-based immunotherapy, we studied successful case ACT where was observed against tumors carrying hotspot mutation G12D KRAS oncogene. Four receptors (TCRs) made up TIL infusion and recognized two KRAS-G12D neoantigens, nonamer...

Natural killer (NK) cells have an important role in immune defense against viruses and cancer. Activation of human NK cell cytotoxicity toward infected or tumor is regulated by immunoglobulin-like receptors (KIRs) that bind to leukocyte antigen class I (HLA-I). Combinations KIR with HLA-I are genetically associated susceptibility disease. KIR2DS4, activating member the family poorly defined ligands, a receptor unknown function. Here, we show KIR2DS4 has strong preference for rare peptides...

IL-8–dependent inflammation is a hallmark of host lung innate immunity to bacterial pathogens, yet in many human diseases, including chronic obstructive pulmonary disease, bronchiectasis, and fibrosis, there are progressive, irreversible, pathological changes associated with elevated levels IL-8 the lung. To better understand duality infection pathology, we expressed transgenically murine bronchial epithelium, investigated impact overexpression on clearance, immunity, pathology function....

Genetic studies associate killer cell immunoglobulin-like receptors (KIRs) and their HLA class I ligands with a variety of human diseases. The basis for these associations the relative contribution inhibitory activating KIR to NK responses are unclear. Because binding HLA-I is peptide dependent, we performed systematic screens, which totaled more than 3500 specific interactions, determine specificity five peptides presented by four HLA-C ligands. Inhibitory KIR2DL1 was largely sequence...

Background. Human natural killer (NK) cell activity is regulated by a family of killer-cell Ig-like receptors (KIR) that bind human leucocyte antigen (HLA) class I. Combinations KIR and HLA genotypes are associated with disease, including susceptibility to viral infection disorders pregnancy. KIR2DL1 binds HLA-C alleles group C2 (Lys80). KIR2DL2 KIR2DL3 C1 (Asn80). However, this model cannot explain allelic effects in disease or the impact HLA-bound peptides. The goal study was determine...

Killer cell immunoglobulin-like receptor/HLA class I (KIR/HLA-I) combinations are associated with disease risk, implicating functional roles for NK cells (NKCs) or KIR(+) T cells. KIR/HLA-I interactions can act through inhibition of NKC activation by target and licensing greater intrinsic responsiveness. We compared conferred the weaker, HLA-C group 1/KIR2DL3, stronger, 2/KIR2DL1, inhibitory combinations. The "rheostat model" predicts weaker HLA-C1/KIR2DL3 than HLA-C2/KIR2DL1. analyzed...

The molecular mechanisms underpinning central nervous system damage in multiple sclerosis (MS) are complex and it is widely accepted that there an autoimmune component. Both adaptive innate immune effector believed to contribute tissue disease aetiology. HLA-E a non-classical MHC class Ib molecule acts as the ligand for NKG2A inhibitory receptor present on natural killer (NK) CD8+ cells. Peptide binding stabilization of often considered signal infection or cell stress. Here we examine...

Dimorphic amino acids at positions 77 and 80 delineate HLA-C allotypes into two groups, C1 C2, which associate with disease through interactions C2-specific natural killer cell receptors. How the C1/C2 dimorphism affects T recognition is unknown. Using that differ only by C1/C2-defining residues, we found KRAS-G12D neoantigen-specific receptors (TCRs) discriminated between C2 presenting same peptides. Structural functional experiments, immunopeptidomics analysis revealed Ser77 in Asn77...

Signaling by immunoreceptors is often initiated phosphorylation of cytosolic tyrosines, which then recruit effector molecules. In the case MHC class I-specific inhibitory receptors, tyrosine residues within ITIMs results in recruitment a protein phosphatase that blocks activation signals. Recent work showed signaling an HLA-C-specific killer cell Ig-like receptor (KIR) independent receptors. It not known how ITIM and regulated. this article, we show substitution His-36 first Ig domain...

Summary Genetic studies associate killer-cell immunoglobulin-like receptors (KIR) and their HLA class I ligands with a variety of human diseases. The basis for these associations, the relative contribution inhibitory activating KIR to NK cell responses are unclear. As binding HLA-I is peptide-dependent, we performed systematic screens totaling over 3,500 specific interactions determine specificity five peptides presented by four HLA-C ligands. Inhibitory KIR2DL1 was largely peptide sequence...

Abstract Complete regression of cancer has been observed in a subset patients following adoptive T-cell transfer (ACT) ex vivo expanded tumor-infiltrating lymphocytes (TIL). However, the low success rate ACT presents great challenge to broader clinical application. To provide rational approach TIL-based immunotherapy, we developed three-pronged comprehensively evaluate clinically relevant traits TIL-TCR. We applied successful case where was against tumors carrying hotspot mutation KRAS-G12D....

Multiple sclerosis is generally considered an autoimmune disease resulting from interaction between predisposing genes and environmental factors, together allowing immunological self-tolerance to be compromised. The precise nature of the inputs has been elusive, infectious agents having received considerable attention. A recent study generated algorithm predicting naturally occurring T cell receptor (TCR) ligands proteome database. Taking example a multiple patient-derived anti-myelin TCR,...

Abstract Mutations in KRAS are some of the most common across multiple cancer types and thus attractive targets for therapy. Recent studies demonstrated that mutant generates immunogenic neoantigens targetable by adoptive T‐cell therapy metastatic diseases. To expand KRAS‐specific immunotherapies, it is critical to identify additional HLA‐I allotypes can present their cognate receptors (TCR). Here, we identified a murine TCR specific KRAS‐G12V neoantigen ( 7 VVVGA V GVGK 16 ) using...

Summary Mutations in KRAS are some of the most common across multiple cancer types and thus attractive targets for therapy. Recent studies demonstrated that mutant generates immunogenic neoantigens can be targeted adoptive T cell therapy metastatic diseases. To expand specific immunotherapies, it is critical to identify additional HLA-I allotypes present their cognate receptors (TCR). Here, we identified a murine TCR KRAS-G12V neoantigen ( 7 VVVGAVGVGK 16 ) using vaccination approach with...

Abstract Natural killer (NK) cells are innate immune effector regulated by many germline-encoded activating and inhibitory receptors. The DAP12-associated receptor KIR2DS4 has been linked with multiple disease processes including cancer, disorders of pregnancy, resistance to HIV. However, the precise ligands for remain poorly defined role this in responses is unclear. Here we show that human a highly peptide-specific MHC-I molecule HLA-C*05:01. Of over 60 different peptides tested, only two...

The killer-cell Ig-like receptor (KIR) family, expressed mainly in natural killer (NK) cells, includes an activation of unknown function, KIR2DS4. Here we show that KIR2DS4 is restricted by HLA-C*05:01 with a strong preference for tryptophan at position 8 9-mer peptides. ‘Self’ peptides Trp8 eluted from are rare and only one out 12 bound An HLA-C*05:01-peptide complex was sufficient primary + NK independently coactivation other receptors prior cell licensing. A highly conserved sequence...

Abstract Background Human natural killer (NK) cell activity is regulated by a family of killer-cell Ig-like receptors (KIR) that bind human leucocyte antigen (HLA) class I. Combinations KIR and HLA genotypes are associated with disease, including susceptibility to viral infection disorders pregnancy. KIR2DL1 binds HLA-C alleles group C2 (Lys 80 ) KIR2DL2 KIR2DL3 C1 (Asn ). However, this model does not capture allelic diversity in or the impact HLA-bound peptides. The goal study was determine...