Cytokine-Mediated Plasticity in the Molecular Requirements for Peptide-Loading Complex Formation and Antigen Presentation
- 1Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
- 2Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Melbourne, VIC 3800, Australia
Abstract
HLA class I antigen presentation depends on coordinated peptide processing, transport and loading, yet inflammatory signalling may modify the consequences of defects in this machinery. We examined wild-type HAP1 cells and isogenic ERAP1-, TAP1- and TAP2-knockout cells before and after interferon-γ (IFNγ) treatment using flow cytometry, proteomics, and immunopeptidomics. IFNγ strongly induced residual antigen-processing machinery in all HAP1-genotypes, increased HLA-I surface expression and expanded peptide recovery, including peptides derived from cancer-associated antigens. However, repertoire restoration was incomplete and defect-specific. ERAP1-deficient cells retained enrichment of longer, terminally extended peptides, whereas TAP2-deficient cells retained alterations in peptide length, processing of peptide flanking regions and source-protein location of the peptide. TAP1-deficient cells showed the greatest convergence to wards wild-type immunopeptidome features upon IFNγ stimulation. Components of the peptide-loading and ER quality-control machinery remained associated with immature HLA-I heavy chains in TAP-deficient cells and were enhanced by exposure to IFNγ. These findings demonstrate that inflammatory signalling can quantitatively and partially qualitatively compensate for defects in HLA-I antigen processing by amplifying intact pathway components and alternative peptide supply, without recreating a fully wild-type immunopeptidome.
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BibTeX
@article{aranha2026cytokinemediated,
title = {{Cytokine-Mediated Plasticity in the Molecular Requirements for Peptide-Loading Complex Formation and Antigen Presentation}},
author = {Ritchlynn Aranha and Mohadeseh Dastpeyman and Kirti Pandey and Mohammadreza Dorvash and Rochelle Ayala and Nathan P. Croft and Anthony W. Purcell},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15201914},
url = {https://www.mdpi.com/2073-4409/15/20/1914},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cytokine-Mediated Plasticity in the Molecular Requirements for Peptide-Loading Complex Formation and Antigen Presentation
AU - Ritchlynn Aranha
AU - Mohadeseh Dastpeyman
AU - Kirti Pandey
AU - Mohammadreza Dorvash
AU - Rochelle Ayala
AU - Nathan P. Croft
AU - Anthony W. Purcell
PY - 2026
DA - 2026/10/21
JO - Cells
DO - 10.3390/cells15201914
UR - https://www.mdpi.com/2073-4409/15/20/1914
AB - HLA class I antigen presentation depends on coordinated peptide processing, transport and loading, yet inflammatory signalling may modify the consequences of defects in this machinery. We examined wild-type HAP1 cells and isogenic ERAP1-, TAP1- and TAP2-knockout cells before and after interferon-γ (IFNγ) treatment using flow cytometry, proteomics, and immunopeptidomics. IFNγ strongly induced residual antigen-processing machinery in all HAP1-genotypes, increased HLA-I surface expression and expanded peptide recovery, including peptides derived from cancer-associated antigens. However, repertoire restoration was incomplete and defect-specific. ERAP1-deficient cells retained enrichment of longer, terminally extended peptides, whereas TAP2-deficient cells retained alterations in peptide length, processing of peptide flanking regions and source-protein location of the peptide. TAP1-deficient cells showed the greatest convergence to wards wild-type immunopeptidome features upon IFNγ stimulation. Components of the peptide-loading and ER quality-control machinery remained associated with immature HLA-I heavy chains in TAP-deficient cells and were enhanced by exposure to IFNγ. These findings demonstrate that inflammatory signalling can quantitatively and partially qualitatively compensate for defects in HLA-I antigen processing by amplifying intact pathway components and alternative peptide supply, without recreating a fully wild-type immunopeptidome.
SN - 2073-4409
ER -