Limited T cell receptor repertoire diversity in tuberculosis patients correlates with clinical severity - PubMed (original) (raw)

Limited T cell receptor repertoire diversity in tuberculosis patients correlates with clinical severity

Wei Luo et al. PLoS One. 2012.

Abstract

Background: The importance of CD4⁺ and CD8⁺ T cells in protection against tuberculosis (TB) is well known, however, the association between changes to the T cell repertoire and disease presentation has never been analyzed. Characterization of T-cells in TB patients in previous study only analyzed the TCR β chain and omitted analysis of the Vα family even though α chain also contribute to antigen recognition. Furthermore, limited information is available regarding the heterogeneity compartment and overall function of the T cells in TB patients as well as the common TCR structural features of Mtb antigen specific T cells among the vast numbers of TB patients.

Methodology/principal findings: CDR3 spectratypes of CD4⁺ and CD8⁺ T cells were analyzed from 86 patients with TB exhibiting differing degrees of disease severity, and CDR3 spectratype complexity scoring system was used to characterize TCR repertoire diversity. TB patients with history of other chronic disease and other bacterial or viral infections were excluded for the study to decrease the likely contribution of TCRs specific to non-TB antigens as far as possible. Each patient was age-matched with a healthy donor group to control for age variability. Results showed that healthy controls had a normally diversified TCR repertoire while TB patients represented with restricted TCR repertoire. Patients with mild disease had the highest diversity of TCR repertoire while severely infected patients had the lowest, which suggest TCR repertoire diversity inversely correlates with disease severity. In addition, TB patients showed preferred usage of certain TCR types and have a bias in the usage of variable (V) and joining (J) gene segments and N nucleotide insertions.

Conclusions/significance: Results from this study promote a better knowledge about the public characteristics of T cells among TB patients and provides new insight into the TCR repertoire associated with clinic presentation in TB patients.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. GeneScan results of partial TCR Vα and Vβ CDR3 products of CD4+ T cell.

(A) PCR products of TCR Vα1-Vα5 of TB patient-1 (mild group) analyzed on a 1.5% agarose gel stained with ethidium bromide. (B) PCR products of TCR Vβ1–Vβ5 of TB patient-1 analyzed on 1.5% agarose gels. (C) Partially fluorescent PCR products of TCR Vα of healthy control-1 analyzed on a 6% acrylamide sequencing gel. (D) CDR3 size and fluorescence intensity analysis of Vα2 and Vα33 of healthy control-1. (E) Partially fluorescent PCR products of TCR Vα of TB patient-1 analyzed on a 6% acrylamide sequencing gel. (F) CDR3 size and fluorescent intensity analysis of Vα17 and Vα34 of TB patient-1.

Figure 2

Figure 2. CDR3 spectratypes of TCR families for CD8+ T cells of TB patient-63 (severe group).

(A**)** The numbers (1–34) denote the corresponding PCR products for TCR families Vα1–Vα34. In the sequencing gel, Lanes 2–7, 10, 20, and 25 include two TCR Vα families in one line. (B) The numbers (1–24) denote the corresponding PCR products of TCR families Vβ1–Vβ24. The lanes with only one bands marked with white arrow.

Figure 3

Figure 3. CDR3 spectratypes of TCR families in CD4+/CD8+ T cells in TB patient-47 (moderate group).

Figure 4

Figure 4. The preferred usage of TCR Vα and Vβ gene families.

The percentage was calculated as the preferred usage frequency of corresponding gene family.

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Grants and funding

This work was supported by grants from National Science and Technology Key Projects on Major Infectious Diseases (2012ZX10003002-007) & National Natural Science Foundation of China (81171539, 30972680) & Key Project of Guangdong Natural Science Foundation (S2011020003154) & Research Fund for the Doctoral Program of Higher Education (20114433110002) & The State Key Laboratory for Molecular Virology and Genetic Engineering (2011KF03). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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