Vaccination and the TAP-independent antigen processing pathways

Abstract

The cytotoxic CD8⁺ T lymphocyte-mediated cellular response is important for the elimination of virus-infected cells and requires the prior recognition of short viral peptide antigens previously translocated to the endoplasmic reticulum by the transporter associated with antigen processing (TAP). However, individuals with nonfunctional TAP complexes or infected cells with TAP molecules blocked by specific viral proteins, such as the cowpoxvirus, a component of the first source of early empirical vaccination against smallpox, are still able to present several HLA class I ligands generated by the TAP-independent antigen processing pathways to specific cytotoxic CD8⁺ T lymphocytes. Currently, bioterrorism and emerging infectious diseases have renewed interest in poxviruses. Recent works that have identified HLA class I ligands and epitopes in virus-infected TAP-deficient cells have implications for the study of both the effectiveness of early empirical vaccination and the analysis of HLA class I antigen processing in TAP-deficient subjects.

Keywords::

• antigen processing
• major histocompatibility complex
• metalloprotease
• poxviruses
• protease inhibitors
• proteasome
• proteolytic enzymes
• T cell
• transporter associated with antigen processing
• vaccine

Financial & competing interests disclosure

This work was supported by a grant provided by the ‘Ministerio de Ciencia e Innovación’ and this funding agency had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • The TAP delivers the viral proteolytic products generated by the proteasome in the cytosol to the ER lumen that are subsequently recognized by cytotoxic T lymphocytes (CTL).

• • Individuals with mutations in the TAP gene that generate non-functional TAP complexes do not seem particularly susceptible to viral infections. Thus, the reduced CTL subpopulation that is specific for TAP-independent antigens may contribute to immune defenses that protect against severe viral infections in these individuals.

• • The eradication of smallpox, a disease caused by variola major virus, was made possible by early empirical, cross-protective vaccination with both cow and horse orthopoxvirus.

• • Cowpox virus specifically inhibits TAP-dependent peptide translocation; therefore, TAP-independent epitopes conserved between variola and this virus probably contributed to the initial cross-protection.

• • Using mass spectrometry to analyze complex HLA-bound peptide pools isolated from large numbers of TAP-deficient, multiple viral ligands naturally presented by different HLA-A, -B, -C and -E class I molecules and conserved among the Orthopoxviridae family were identified.

• • Two of four epitopes (including the immunodominant epitope) detected in the standard antiviral response from the H-2 class I double-knockout HLA-B*07-transgenic mice were presented by TAP-independent pathways. Thus, TAP-independent HLA-B*07 antigen presentation could be sufficient to control orthopoxvirus infection in the absence of a functional TAP complex.

• • The existence of multiple TAP-independent orthopoxvirus ligands generated by multiple proteases in complex antigen processing and presentation routes, which operate in the absence of the TAP-dependent classical pathway, suggests that these pathways could be a secondary but extended and relevant mechanism of immune protection against viral infection, but this hypothesis requires further investigation in vivo.