MHC class II peptide flanking residues of exogenous antigens influence recognition by autoreactive T cells

Area of Science:

• Immunology
• Microbiology
• Neuroscience

Background:

• Molecular mimicry is a proposed mechanism for autoimmune disease initiation.
• Chlamydia pneumoniae infection has been implicated in autoimmune conditions.
• Experimental autoimmune encephalomyelitis (EAE) is a model for human autoimmune neurological diseases.

Purpose of the Study:

• To investigate the role of molecular mimicry between Chlamydia pneumoniae and self-antigens in EAE.
• To determine the specific interactions of microbial and self-peptides with T cell receptors (TCRs) and MHC molecules.
• To elucidate how peptide modifications affect encephalitogenic activity and T cell recognition.

Main Methods:

• Induction of EAE in Lewis rats using a Chlamydia pneumoniae peptide (Cpn0483) and a rat myelin basic protein peptide (rat68-86).
• Analysis of TCR contact residues and MHC class II restriction.
• T cell proliferation assays using native peptides and analogs (CpnN>A).

Main Results:

• Cpn0483 peptide shares a motif with rat68-86 and elicits EAE in Lewis rats, restricted by MHC class II RT1.B(l).
• Distinct TCR contact residues were identified for rat68-86 (D, R) and Cpn0483 (R, N).
• T cells primed with Cpn0483 proliferated to both Cpn0483 and CpnN>A, but CpnN>A-primed T cells did not respond to Cpn0483, indicating the influence of the C-terminal asparagine.

Conclusions:

• The C-terminal asparagine residue in the Chlamydia pneumoniae peptide significantly influences T cell recognition.
• Structural differences in peptide-MHC interactions can dictate encephalitogenic potential despite shared motifs.
• This study highlights the complexity of molecular mimicry in triggering autoimmune responses.