The same major histocompatibility complex polymorphism involved in control of HIV influences peptide binding in the mouse H-2Ld system.
Single-site polymorphisms in human class I major histocompatibility complex (MHC) products (HLA-B) have recently been shown to correlate with HIV disease progression or control. An identical single-site polymorphism (at residue 97) in the mouse class I product H-2L(d) influences stability of the complex. To gain insight into the human polymorphisms, here we examined peptide binding, stability, and structures of the corresponding L(d) polymorphisms, Trp(97) and Arg(97). Expression of L(d)W97 and L(d)R97 genes in a cell line that is antigen-processing competent showed that L(d)R97 was expressed at higher levels than L(d)W97, consistent with enhanced stability of self-peptide·L(d)R97 complexes. To further examine peptide-binding capacities of these two allelic variants, we used a high affinity pep-L(d) specific probe to quantitatively examine a collection of self- and foreign peptides that bind to L(d). L(d)R97 bound more effectively than L(d)W97 to most peptides, although L(d)W97 bound more effectively to two peptides. The results support the view that many self-peptides in the L(d) system (or the HLA-B system) would exhibit enhanced binding to Arg(97) alleles compared with Trp(97) alleles. Accordingly, the self-peptide·MHC-Arg(97) complexes would influence T-cell selection behavior, impacting the T-cell repertoire of these individuals, and could also impact peripheral T cell activity through effects of self-peptide·L(d) interacting with TCR and/or CD8. The structures of several peptide·L(d)R97 and peptide·L(d)W97 complexes provided a framework of how this single polymorphism could impact peptide binding.
From the Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801.
Samanthi
S
Narayanan
David M
DM
Kranz
D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D060966:Clonal Selection, Antigen-Mediated / Q000502:physiology; D006678:HIV; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D064532:Histocompatibility Antigen H-2D / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D011110:Polymorphism, Genetic / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D015235:HLA-B Antigens; D064532:Histocompatibility Antigen H-2D; D010455:Peptides
Antigen; Antigen Presentation; HIV; Major Histocompatibility Complex (MHC); T Cell