Evidence for Highly Variable, Region-Specific Patterns of T-Cell Epitope Mutations Accumulating in Mycobacterium...

Area of Science:

• Immunology
• Genomics
• Microbiology

Background:

• Adaptive T-cell immunity is crucial for vaccines against tuberculosis (TB).
• Understanding T-cell epitope (TCE) evolution and immune escape mechanisms in Mycobacterium tuberculosis (Mtb) is vital for TB vaccine development.
• CD4 T-cell responses are particularly important in TB immunity.

Purpose of the Study:

• To investigate the evolution of CD4 T-cell epitopes (TCEs) in Mycobacterium tuberculosis (Mtb) strains from India.
• To identify mutated TCEs (mTCEs) associated with immune escape.
• To assess the functional impact of these mTCEs on T-cell responses and their potential role in TB vaccine design.

Main Methods:

• Screened 905 human CD4 T-cell epitopes against 79 Mtb whole genomes from India.
• Identified mutated epitopes using a computational pipeline and single nucleotide polymorphism (SNP) analysis.
• Analyzed mTCE prevalence in a global SNP database and assessed their impact on CD4 T-cell cytokine secretion (IFNγ, IL2) and HLA-DR binding affinity.

Main Results:

• Identified 64 mutated T-cell epitopes (mTCEs) in Indian Mtb strains, with 89% being novel.
• Demonstrated that 62% of tested mTCEs significantly altered CD4 T-cell IFNγ and/or IL2 secretion, correlating with predicted HLA-DR binding affinity.
• Found 82% of mTCEs were more prevalent in Indian Mtb strains, with 36 mTCEs exclusive to India, and higher binding affinity to India-prevalent HLA-DR alleles.

Conclusions:

• Identified region-specific TCE mutations in Mtb strains from India, suggesting a mechanism for immune escape.
• These findings highlight the potential role of HLA-DR allele prevalence in driving TCE mutations.
• The identified mTCEs have significant implications for the design of effective TB vaccines.