The cellular redox environment alters antigen presentation

Area of Science:

• Immunology
• Biochemistry
• Proteomics

Background:

• Cysteine-containing peptides are crucial T cell epitopes but their prevalence is underestimated.
• Naturally processed peptides bound to MHC molecules are key to T cell recognition.

Purpose of the Study:

• To quantify the prevalence and modifications of cysteine-containing peptides in the immunopeptidome.
• To investigate the role of oxidative stress and glutathione modification in T cell recognition during viral infections.

Main Methods:

• Analysis of a large database (~70,000) of naturally processed MHC-bound peptides.
• Identification and characterization of oxidative modifications on cysteine residues.
• Assessment of T cell recognition of modified viral peptides.

Main Results:

• Cysteine-containing peptides constitute 5-10% of the immunopeptidome, presented in an MHC allomorph-dependent manner.
• A significant fraction of these peptides undergo S-glutathionylation, a physiological modification.
• Glutathione modification of viral peptides alters T cell recognition, linking cellular redox state to immune signaling.

Conclusions:

• Oxidative stress, specifically S-glutathionylation, is a physiological mechanism modulating T cell responses to viral infections.
• This modification provides a structural basis for altered T cell recognition.
• The findings highlight the underappreciated role of cysteine modifications in adaptive immunity.