Search

Human leukocyte antigen (HLA) alleles have a high degree of polymorphism, which determines their peptide-binding motifs and subsequent T-cell receptor recognition. The simplest way to understand the cross-presentation of peptides by different alleles is to classify these alleles into supertypes. A1 and A3 HLA supertypes are widely distributed in humans. However, direct structural and functional evidence for peptide presentation features of key alleles (e.g., HLA-A*30:01 and -A*30:03) are lacking. Herein, the molecular basis of peptide presentation of HLA-A*30:01 and -A*30:03 was demonstrated by crystal structure determination and thermostability measurements of complexes with T-cell epitopes from influenza virus (NP44), human immunodeficiency virus (RT313), and Mycobacterium tuberculosis (MTB). When binding to the HIV peptide, RT313, the PΩ-Lys anchoring modes of HLA-A*30:01, and -A*30:03 were similar to those of HLA-A*11:01 in the A3 supertype. However, HLA-A*30:03, but not -A*30:01, also showed binding with the HLA*01:01-favored peptide, NP44, but with a specific structural conformation. Thus, different from our previous understanding, HLA-A*30:01 and -A*30:03 have specific peptide-binding characteristics that may lead to their distinct supertype-featured binding peptide motifs. Moreover, we also found that residue 77 in the F pocket was one of the key residues for the divergent peptide presentation characteristics of HLA-A*30:01 and -A*30:03. Interchanging residue 77 between HLA-A*30:01 and HLA-A*30:03 switched their presented peptide profiles. Our results provide important recommendations for screening virus and tumor-specific peptides among the population with prevalent HLA supertypes for vaccine development and immune interventions.

Human leukocyte antigen (HLA) alleles have a high degree of polymorphism, which determines their peptide-binding motifs and subsequent T-cell receptor recognition. The simplest way to understand the cross-presentation of peptides by different alleles is to classify these alleles into supertypes. A1 and A3 HLA supertypes are widely distributed in humans. However, direct structural and functional evidence for peptide presentation features of key alleles (e.g., HLA-A*30:01 and -A*30:03) are lacking. Herein, the molecular basis of peptide presentation of HLA-A*30:01 and -A*30:03 was demonstrated by crystal structure determination and thermostability measurements of complexes with T-cell epitopes from influenza virus (NP44), human immunodeficiency virus (RT313), and Mycobacterium tuberculosis (MTB). When binding to the HIV peptide, RT313, the PΩ-Lys anchoring modes of HLA-A*30:01, and -A*30:03 were similar to those of HLA-A*11:01 in the A3 supertype. However, HLA-A*30:03, but not -A*30:01, also showed binding with the HLA*01:01-favored peptide, NP44, but with a specific structural conformation. Thus, different from our previous understanding, HLA-A*30:01 and -A*30:03 have specific peptide-binding characteristics that may lead to their distinct supertype-featured binding peptide motifs. Moreover, we also found that residue 77 in the F pocket was one of the key residues for the divergent peptide presentation characteristics of HLA-A*30:01 and -A*30:03. Interchanging residue 77 between HLA-A*30:01 and HLA-A*30:03 switched their presented peptide profiles. Our results provide important recommendations for screening virus and tumor-specific peptides among the population with prevalent HLA supertypes for vaccine development and immune interventions. [ABSTRACT FROM AUTHOR]

KIR3DL2/CD158k/p140 is a 3 domain killer cell immunoglobulin-like receptor incorporating cytoplasmic ITIM motifs, expressed as a disulphide-bonded dimer. KIR3DL2 is a framework gene within the KIR locus and is highly polymorphic, with 62 allelic variants possibly coding for protein reported. KIR3DL2 binds to HLA-A3 and A11 in a peptide-dependent fashion and to B27 free heavy chain forms. In addition, KIR3DL2 can also function as an innate immune receptor for delivery of CpG DNA to TLR9 in NK cells. The increased levels of expression of KIR3DL2 compared with other KIR expressed by T cell subsets in healthy individuals suggest it may function as a default KIR receptor. KIR3DL2-expressing natural killer cells and IL17 secreting CD4 T cells have been implicated in the pathogenesis of ankylosing spondylitis. Moreover, KIR3DL2 expression delineates circulating and cutaneous lymphoma T cells in Sezary’s syndrome.Here I discuss how the unique molecular attributes of KIR3DL2 impact on its function on NK and T cells and how this may relate to its role in disease.

KIR3DL2/CD158k/p140 is a three domain killer cell immunoglobulin-like receptor incorporating cytoplasmic immunoreceptor tyrosine inhibitory motifs, expressed as a disulphide-bonded dimer. KIR3DL2isaframework gene within the KIR locus andishighly polymorphic, with 62 allelic variants possibly coding for protein reported. KIR3DL2 binds to HLA-A3 and -A11 in a peptide-dependent fashion and to B27 free heavy chain forms. In addition, KIR3DL2 can also function as an innate immune receptor for delivery of CpG DNA toTLR9 in NK cells. The increased levels of expression of KIR3DL2 compared with other KIR expressed byT cell subsets in healthy individuals suggest it may function as a default KIR receptor. KIR3DL2-expressing natural killer (NK) cells and IL17 secreting CD4 T cells have been implicated in the pathogenesis of ankylosing spondylitis. Moreover, KIR3DL2 expression delineates circulating and cutaneous lymphoma T cells in Sézary's syndrome. Here we discuss how the unique molecular attributes of KIR3DL2 impact on its function on NK and T cells and how this may relate to its role in disease [ABSTRACT FROM AUTHOR]