stability-structure-bat-major-histocompatibility-complex-class-i-with

Stability and Structure of Bat Major Histocompatibility Complex Class I with Heterologous &beta;<sub>2</sub>-Microglobulin

The major histocompatibility complex (MHC) plays a pivotal role in antigen peptide presentation and T cell immune responses against infectious disease and ...

Chinese Center For Disease Control And Prevention

University of Chinese Academy of Sciences

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-A30:01 and -A30:03) are lacking. Herein, the molecular basis of peptide presentation of HLA-A30:01 and -A30:03 was demonstrated by crystal structure determination and thermostability measurements of complexes with T-cell epitopes from influenza virus (NP44), human immunodeficiency virus (RT313), and  (MTB). When binding to the HIV peptide, RT313, the PΩ-Lys anchoring modes of HLA-A30:01, and -A30:03 were similar to those of HLA-A11:01 in the A3 supertype. However, HLA-A30:03, but not -A30:01, also showed binding with the HLA01:01-favored peptide, NP44, but with a specific structural conformation. Thus, different from our previous understanding, HLA-A30:01 and -A30:03 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-A30:01 and -A30:03. Interchanging residue 77 between HLA-A30:01 and HLA-A30:03 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.

Divergent Peptide Presentations of HLA-A30 Alleles Revealed by Structures With Pathogen Peptides.

Bats harbor many zoonotic viruses, including highly pathogenic viruses of humans and other mammals, but they are typically asymptomatic in bats. To further understand the antiviral immunity of bats, we screened and identified a series of bat major histocompatibility complex (MHC) I Ptal-N*01:01-binding peptides derived from four different bat-borne viruses, i.e., Hendra virus (HeV), Ebola virus (EBOV), Middle East respiratory syndrome coronavirus (MERS-CoV), and H17N10 influenza-like virus. The structures of Ptal-N*01:01 display unusual peptide presentation features in that the bat-specific 3-amino acid (aa) insertion enables the tight "surface anchoring" of the P1-Asp in pocket A of bat MHC I. As the classical primary anchoring positions, the B and F pockets of Ptal-N*01:01 also show unconventional conformations, which contribute to unusual peptide motifs and distinct peptide presentation. Notably, the features of bat MHC I may be shared by MHC I from various marsupials. Our study sheds light on bat adaptive immunity and may benefit future vaccine development against bat-borne viruses of high impact on humans.

Peptide presentation by bat MHC class I provides new insight into the antiviral immunity of bats.

Rabbits are pivotal domestic animals for both the economy and as an animal model for human diseases. A large number of rabbits have been infected by rabbit hemorrhagic disease virus (RHDV) in natural and artificial pandemics in the past. Differences in presentation of antigenic peptides by polymorphic major histocompatibility complex (MHC) molecules to T-cell receptors (TCR) on T lymphocytes are associated with viral clearance in mammals. Here, we screened and identified a series of peptides derived from RHDV binding to the rabbit MHC class I molecule, RLA-A1. The small, hydrophobic B and F pockets of RLA-A1 capture a peptide motif analogous to that recognized by human class I molecule HLA-A*0201, with more restricted aliphatic anchors at P2 and PΩ positions. Moreover, the rabbit molecule is characterized by an uncommon residue combination of Gly53, Val55, and Glu56, making the 3 helix and the loop between the 3 and α1 helices closer to the α2 helix. A wider A pocket in RLA-A1 can induce a special conformation of the P1 anchor and may play a pivotal role in peptide assembly and TCR recognition. Our study broadens the knowledge of T-cell immunity in domestic animals and also provides useful insights for vaccine development to prevent infectious diseases in rabbits. We screened rabbit MHC class I RLA-A1-restricted peptides from the capsid protein VP60 of rabbit hemorrhagic disease virus (RHDV) and determined the structures of RLA-A1 complexed with three peptides, VP60-1, VP60-2, and VP60-10. From the structures, we found that the peptide binding motifs of RLA-A1 are extremely constraining. Thus, there is a generally restricted peptide selection for RLA-A1 compared to that for human HLA-A*0201. In addition, uncommon residues Gly53, Val55, and Glu56 of RLA-A1 are located between the 3 helix and α1 helix, which makes the steric position of the 3 helix in RLA-A1 much closer to the α2 helix than that found in other mammalian MHC class I molecules. This special conformation between the 3 helix and α1 helix plays a pivotal role in rabbit MHC class I assembly. Our results provide new insights into MHC class I molecule assembly and peptide presentation of domestic mammals. Furthermore, these data also broaden our knowledge on T-cell immunity in rabbits and may also provide useful information for vaccine development to prevent infectious diseases in rabbits.

Strict Assembly Restriction of Peptides from Rabbit Hemorrhagic Disease Virus Presented by Rabbit Major Histocompatibility Complex Class I Molecule RLA-A1.

Dan Lu

NHC Key Laboratory of Biosafety,
National Institute for Viral Disease Control and Prevention,
NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention

Chinese Center For Disease Control And Prevention

Stability and Structure of Bat Major Histocompatibility Complex Class I with Heterologous β₂-Microglobulin

Dan Lu

NHC Key Laboratory of Biosafety,National Institute for Viral Disease Control and Prevention,NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention

Chinese Center For Disease Control And Prevention

Stability and Structure of Bat Major Histocompatibility Complex Class I with Heterologous β2-Microglobulin

NHC Key Laboratory of Biosafety,
National Institute for Viral Disease Control and Prevention,
NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention

Stability and Structure of Bat Major Histocompatibility Complex Class I with Heterologous β₂-Microglobulin