Abstract

Induction of an effective tumor immunity is a complex process that includes the appropriate presentation of the tumor antigens, activation of specific T cells, and the elimination of malignant cells. Potent and efficient T cell activation is dependent on multiple factors, such as timely expression of co-stimulatory molecules, the differentiation state of professional antigen presenting cells (e.g., dendritic cells; DCs), the functionality of the antigen processing and presentation machinery (APPM), and the repertoire of HLA class I and II-bound peptides (termed immunopeptidome) presented to T cells. So far, how molecular perturbations underlying DCs maturation and differentiation affect the in vivo cross-presented HLA class I and II immunopeptidomes is largely unknown. Yet, this knowledge is crucial for further development of DC-based immunotherapy approaches. We applied a state-of-the-art sensitive MS-based immunopeptidomics approach to characterize the naturally presented HLA-I and -II immunopeptidomes eluted from autologous immune cells having distinct functional and biological states including CD14+ monocytes, immature DC (ImmDC) and mature DC (MaDC) monocyte-derived DCs and naive or activated T and B cells. We revealed a presentation of significantly longer HLA peptides upon activation that is HLA allotype specific. This was apparent in the self-peptidome upon cell activation and in the context of presentation of exogenously loaded antigens, suggesting that peptide length is an important feature with potential implications on the rational design of anti-cancer vaccines.

Highlights

  • The primary aim of the adaptive immune system is to provide highly specific response against “non-self ” antigens and generate memory to counter similar insults in the future [1]

  • Proteins located above the lines are statistically significantly modulated in their level of expression (FDR = 0.01, S0 = 3). (C) Human Leukocyte Antigen (HLA)-I and HLA class II (HLA-II) uniquely identified peptides identified for CD14+, immature Dendritic cells (DCs) and mature DC. (D) Proteome remodeling during DC maturation influences the repertoire of the HLA class IImmunopeptidomics of Activated Immune Cells (HLA-I) peptidome

  • The blue dots represent HLA-I peptides which belong to all source proteins found upregulated upon maturation in the proteomics analysis

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Summary

Introduction

The primary aim of the adaptive immune system is to provide highly specific response against “non-self ” antigens and generate memory to counter similar insults in the future [1]. Intracellular degradation of proteins generates short peptides that are transferred into the Endoplasmic reticulum where they can be presented in complex with the HLA class I. Exogenous antigens can be processed within the DCs and presented on HLA-II complexes and in a process known as cross-presentation, they can be presented on HLA class I molecules [3, 4]. Due to these unique properties, DCs are the most potent primers of naïve T cells and they are essentially the master regulators of immune system [5]

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