CD8(+) T cells are essential for host defense to intracellular bacterial pathogens such as Mycobacterium tuberculosis (Mtb), Salmonella species, and Listeria monocytogenes, yet the repertoire and dominance pattern of human
CD8 antigens for these pathogens remains poorly characterized.
Tuberculosis (TB), the disease caused by Mtb
infection, remains one of the leading causes of infectious morbidity and mortality worldwide and is the most frequent
opportunistic infection in individuals with HIV/
AIDS. Therefore, we undertook this study to define immunodominant CD8 Mtb
antigens. First, using IFN-gamma ELISPOT and synthetic
peptide arrays as a source of
antigen, we measured ex vivo frequencies of CD8(+) T cells recognizing known immunodominant CD4(+) T cell
antigens in persons with
latent tuberculosis infection. In addition, limiting dilution was used to generate panels of Mtb-specific T cell clones. Using the
peptide arrays, we identified the
antigenic specificity of the majority of T cell clones, defining several new
epitopes. In all cases,
peptide representing the minimal
epitope bound to the major histocompatibility complex (MHC)-restricting allele with high affinity, and in all but one case the restricting allele was an
HLA-B allele. Furthermore, individuals from whom the T cell clone was isolated harbored high ex vivo frequency CD8(+) T cell responses specific for the
epitope, and in individuals tested, the
epitope represented the single immunodominant response within the
CD8 antigen. We conclude that Mtb-specific CD8(+) T cells are found in high frequency in infected individuals and are restricted predominantly by
HLA-B alleles, and that synthetic
peptide arrays can be used to define
epitope specificities without prior bias as to MHC binding affinity. These findings provide an improved understanding of immunodominance in humans and may contribute to a development of an effective TB
vaccine and improved immunodiagnostics.