Abstract
HLA class I (HLA-I) transgenic mice have proven to be useful models for studying human MHC-related immune responses over the last two decades. However, differences in the processing and presentation machinery between humans and mice may have profound effects on HLA-I restricted antigen presentation. In this study, we generated a novel human TAP-LMP (hTAP-LMP) gene cluster transgenic mouse model carrying an intact human TAP complex and two human immunoproteasome LMP subunits, PSMB8/PSMB9. By crossing the hTAP-LMP strain with different HLA-I transgenic mice, we found that the expression levels of human HLA-I molecules, especially the A3 supertype members (e.g., A11 and A33), were remarkably enhanced in corresponding HLA-I/hTAP-LMP transgenic mice. Moreover, we found that humanized processing and presentation machinery increased antigen presentation of HLA-A11-restricted epitopes and promoted the rapid reduction of hepatitis B virus (HBV) infection in HLA-A11/hTAP-LMP mice. Together, our study highlights that HLA-I/hTAP-LMP mice are an improved model for studying antigen presentation of HLA-I molecules and their related CTL responses.
Highlights
Human leukocyte antigen class I (HLA-I) molecules that present antigenic peptides to CD8+ T cells and trigger the cytotoxic T lymphocyte (CTL) response are essential for the human immune system to combat viral infections and clear transformed tumor cells[1,2]
In both humans and mice, the MHC class I antigen presentation pathway proceeds through several stages[9,10]: i) endogenous proteins in the cytosol are degraded into short peptides of 3–22 residues by the proteasome or immunoproteasome; ii) peptide products of 8–12 amino acids are transported into the endoplasmic reticulum (ER) by a dimer complex, the transporter associated with antigen processing (TAP); and iii) empty MHC class I molecules in the ER are stabilized by binding to suitable peptides to form peptide-MHC complexes, which are exported to the cell surface for presentation to CD8+ T cells
We found that the expression levels of human HLA class I (HLA-I), especially the A3 supertype, and the HLA-A11-restricted CTL response were notably enhanced by expression of the humanized processing and presenting machinery
Summary
Human leukocyte antigen class I (HLA-I) molecules that present antigenic peptides to CD8+ T cells and trigger the cytotoxic T lymphocyte (CTL) response are essential for the human immune system to combat viral infections and clear transformed tumor cells[1,2]. Epitopes with high TAP affinity can to be selected and recognized by CTLs. Interestingly, the peptide binding specificities between human and mouse TAP are quite different. Nine major HLA-I supertypes are classified according to their structural similarities in the antigen binding groove and overlapping peptide binding properties[25] Among these supertypes, B7, A3, A2, A24, B44, A1, and B27 are the most prevalent in different ethnic groups[25]. HLA-A3, A24, and B27 binding peptides have higher affinity for human TAP than that of HLA-A2 and B726, supporting the notion that particular HLA-I molecules co-evolved with TAP for efficient peptide processing and presentation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
