T cell receptor αβ diversity inversely correlates with pathogen-specific antibody levels in human cytomegalovirus infection - PubMed (original) (raw)

T cell receptor αβ diversity inversely correlates with pathogen-specific antibody levels in human cytomegalovirus infection

George C Wang et al. Sci Transl Med. 2012.

Abstract

A diverse T cell receptor (TCR) repertoire capable of recognizing a broad range of antigenic peptides is thought to be central to effective pathogen-specific immunity by counteracting escape mutations, selecting high-avidity T cells, and providing T cell specificities with comprehensive functional characteristics. However, evidence that TCR diversity is important for the successful control of human infections is limited. A single-cell strategy for the clonotypic analysis of human CD8⁺ TCRαβ repertoires was used to probe the diversity and magnitude of individual human cytomegalovirus (CMV)-specific CD8⁺ T cells recovered directly ex vivo. We found that CD8⁺ TCRαβ repertoire diversity, but not the size of the CD8⁺ T cell response, was inversely related to circulating CMV-specific antibody levels, a measure that has been correlated epidemiologically with differential mortality risks and found here to be higher in persons with detectable (versus undetectable) CMV viral loads. Overall, our findings indicate that CD8⁺ T cell diversity may be more important than T cell abundance in limiting the negative consequences of CMV persistence, demonstrate high prevalence of both TCRα and TCRβ public motif usage, and suggest that a highly diverse TCRαβ repertoire may be an important benchmark and target in the success of immunotherapeutic strategies.

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Figures

Fig. 1

Fig. 1

Overview of single-cell multiplex clonotypic analysis of epitope-specific T cells. Single epitope-specific CD8+ T cells are sorted on a flow cytometric cell sorter into 96-well PCR plates. RT-PCR is performed on the individual cells. The resultant cDNA is subjected to two rounds of nested PCR. In the first round, CDR3α and CDR3β transcript amplification is achieved with the use of a multiplexed, comprehensive panel of external sense Vα and Vβ and antisense Cα and Cβ segment-specific primers. First-round PCR products are subjected to two separate second-round PCRs, incorporating, respectively, a multiplexed panel of external sense Vα and antisense Cα or external sense Vβ and antisense Cβ segment-specific primers. PCR products thus derived are sequenced and translated to yield paired CDR3αβ repertoire data. Inset: Nucleotide products from nested PCR performed on cDNA derived from single CMV-NLV-specific CD8+ T cells from a young adult donor, incorporating TCRα- (top 2 rows) and TCRβ-specific primers (bottom 2 rows).

Fig. 2

Fig. 2

Relationships between paired CDR3α and CDR3β sequences in CMV-NLV-specific CD8 T-cell repertoire. (A) Prevalence of CDR3α and CDR3β public motif usage among all responses. Percentages were derived from paired CDR3αβ data (N = 135 TCR sequences). (B) and (C) Relationships between hydrophobicity (B) or polarity (C) values within paired CDR3α and CDR3β amino acid sequences. Hydrophobicity and polarity are defined in the text. In (B) and (C), each symbol represents one CDR3αβ pair. Correlation was assessed using the Spearman's rank correlation coefficient. Percentages do not total 100% due to rounding error.

Fig. 3

Fig. 3

Relationship between CMV-NLV-specific CTL response and serum anti-CMV IgG concentration. (A) Relationship between CMV-NLV-specific CD8+ TCRαβ repertoire diversity, expressed as the Simpson's Diversity Index (SDI; see text and footnote to Table 2), and CMV IgG concentration. (B) Examination of the CMV-NLV-specific CD8+ TCRα and TCRβ repertoire diversities, as separate variables, in relationship with the CMV IgG concentration. (C) Relationship between the magnitude of the CTL response, measured as the frequency of CMV-NLV pMCHI tetramer+ CD8+ T cells (as percentage of all CD8+ T cells), and the CMV IgG concentration. Correlation was assessed using the Spearman's rank correlation coefficient. Each TCR repertoire was measured in 1 experiment per donor. CMV IgG concentration was measured in duplicates.

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