Immunodominant cytomegalovirus-specific CD8+ T-cell responses in sub-Saharan African populations

Abstract

More than 90% of children in Africa are infected with cytomegalovirus (CMV) by the age of 12 months. However, the high-frequency, immunodominant CD8+ T-cell responses that control CMV infection have not been well studied in African populations. We therefore sought to define the immunodominant CMV-specific CD8+ T-cell responses within sub-Saharan African study subjects. Among 257 subjects, we determined the CD8+ T-cell responses to overlapping peptides spanning three of the most immunogenic CMV proteins, pp65, IE-1 and IE-2, using IFN-γ ELISpot assays. A bioinformatics tool was used to predict optimal epitopes within overlapping peptides whose recognition was statistically associated with expression of particular HLA class I molecules. Using this approach, we identified 16 predicted novel CMV-specific epitopes within CMV-pp65, IE-1 and IE-2. The immunodominant pp65-specific, IE-1, IE-2 responses were all either previously well characterised or were confirmed using peptide-MHC tetramers. The novel epitopes identified included an IE-2-specific epitope restricted by HLA*B*44:03 that induced high-frequency CD8+ T-cell responses (mean 3.4% of CD8+ T-cells) in 95% of HLA-B*44:03-positive subjects tested, in one individual accounting for 18.8% of all CD8+ T-cells. These predicted novel CMV-specific CD8+ T-cell epitopes identified in an African cohort will facilitate future analyses of immune responses in African populations where CMV infection is almost universal during infancy.

Major TCR Repertoire Perturbation by Immunodominant HLA-B*44:03-Restricted CMV-Specific T Cells

“…The unusual magnitude of the HLA-B * 44:03-restricted NW8-specific CD8+ T cell response deserves comment. In most individuals, >3% of CD8+ T cells, and in one individual almost 1 in 5 CD8+ T cells (19%), are specific for this single response ( 22 ). Even by the standards of CMV-specific CD8+ T cell responses, which are renowned to be very large, this is an exceptional example.…”

“…We recently characterised an immunodominant CMV-specific response in African populations that is restricted by HLA-B * 44:03 ( 22 ). This class I molecule is expressed in ~15% of African populations ( 23 ) and differs by a single amino acid from the closely related HLA-B * 44:02 ( 24 ), the most prevalent HLA-B * 44 subtype in Caucasian populations.…”

Cytomegalovirus-Mediated T Cell Receptor Repertoire Perturbation Is Present in Early Life

“…Lastly, this increasing inequality in clone sizes is thought to have functional consequences, which effectively translate to increased susceptibility to infectious disease (14). We recently described a paragon of virally-induced TCR repertoire distortion by showing that CMV-infected HLA-B * 44:03 individuals possessed large oligo/monoclonal expansions of superdominant clones (25,26). Thus, in this setting, the immunological space available to tackle pathogens other than CMV may be significantly compromised by the extent of such TCR repertoire skewing (27).…”

“…We previously showed that HLA-B * 44:03 subjects mounted a robust CD8 T cell response against the immediate-early-2 (IE-2)derived epitope NEGVKAAW (NW8) (25), with drastic clonal expansion of superdominant TCR clonotypes (26). This finding led us to the hypothesis that TCR superdominance may be a feature of "memory inflation" occurring as a result of gradual expansion of antigen-specific T cells over time.…”

High-intensity interval training in allogeneic adoptive T-cell immunotherapy – a big HIT?

“…HIT appears to augment IFN-γ secretion, especially in the case of circulating memory VSTs with low precursor frequencies, like AdV-specific T cells [46]. Conversely, T cells against the highly immunodominant antigen CMV pp65 [54], which have higher frequencies in the circulation of healthy donors, did not respond as much to exercise. This finding suggests that HIT is most beneficial for boosting antigen-specific T cells with low precursor frequencies.…”