Abstract:
High-tuberculosis (TB)-burden countries are located in sub-Saharan Africa. We examined the frequency
of human leukocyte antigen (HLA) alleles, followed by recombinant expression of the most frequent
HLA-A alleles, i.e., HLA-A*3001 and HLA-A*3002, to study differences in mycobacterial peptide presentation
and CD8 T-cell recognition. We screened a peptide library (9-mer peptides with an 8-amino-acid
overlap) for binding, affinity, and off-rate of the Mycobacterium tuberculosis-associated antigen TB10.4 and
identified only three TB10.4 peptides with considerable binding to HLA-A*3001. In contrast, 22 peptides
bound to HLA-A*3002. This reflects a marked difference in the binding preference between the two alleles,
with A*3002 tolerating a more promiscuous peptide-binding pattern and A*3001 accommodating only a
very selective peptide repertoire. Subsequent analysis of the affinity and off-rate of the binding peptides
revealed a strong affinity (8 nM to 7 M) and moderate off-rate (20 min to 3 h) for both alleles.
Construction of HLA-A*3001 and HLA-A*3002 tetramers containing selected binding peptides from
TB10.4, including a peptide which was shared among both alleles, QIMYNYPAM (TB10.43–11), allowed us
to enumerate epitope-specific T cells in HLA-A*3001- and HLA-A*3002-typed patients with active TB.
HLA-A*3001 and HLA-A*3002 major histocompatibility complex-peptide complexes were recognized in
individuals with active TB, irrespective of their homozygous HLA-A*3001 or HLA-A*3002 genetic background.
The antigen-specific T cells exhibited the CD45RA CCR7 precursor phenotype and the interleukin-
7 receptor (CD127), which were different from the phenotype and receptor exhibited by the parental
CD8 T-cell population.
