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Infection and Immunity, December 2009, p. 5486-5495, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.01436-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Frequencies of Region of Difference 1 Antigen-Specific but Not Purified Protein Derivative-Specific Gamma Interferon-Secreting T Cells Correlate with the Presence of Tuberculosis Disease but Do Not Distinguish Recent from Remote Latent Infections{triangledown}

Timothy S. C. Hinks,1,2 Davinder P. S. Dosanjh,2 John A. Innes,3 Geoffrey Pasvol,4 Sarah Hackforth,3 Hansa Varia,4 Kerry A. Millington,2 Xiao-Qing Liu,5 Mustafa Bakir,6 Ahmet Soysal,6 Robert N. Davidson,4 Rubamalar Gunatheesan,2 and Ajit Lalvani2*

Division of Infection, Inflammation, Immunity, Mailpoint 810, University of Southampton School of Medicine, Southampton General Hospital, Southampton SO16 6YD, United Kingdom,1 Tuberculosis Research Unit, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, St. Mary's Campus, Norfolk Place, London W2 1PG, United Kingdom,2 Department of Infection & Tropical Medicine, Birmingham Heartlands Hospital, Birmingham, United Kingdom,3 Department of Infection and Tropical Medicine, Northwick Park Hospital, Harrow, United Kingdom,4 Peking Union Medical College Hospital, Beijing, China,5 Department of Paediatrics, Marmara University School of Medicine, Istanbul, Turkey6

Received 22 November 2008/ Returned for modification 5 February 2009/ Accepted 19 August 2009

The majority of individuals infected with Mycobacterium tuberculosis achieve lifelong immune containment of the bacillus. What constitutes this effective host immune response is poorly understood. We compared the frequencies of gamma interferon (IFN-{gamma})-secreting T cells specific for five region of difference 1 (RD1)-encoded antigens and one DosR-encoded antigen in 205 individuals either with active disease (n = 167), whose immune responses had failed to contain the bacillus, or with remotely acquired latent infection (n = 38), who had successfully achieved immune control, and a further 149 individuals with recently acquired asymptomatic infection. When subjects with an IFN-{gamma} enzyme-linked immunospot (ELISpot) assay response to one or more RD1-encoded antigens were analyzed, T cells from subjects with active disease recognized more pools of peptides from these antigens than T cells from subjects with nonrecent latent infection (P = 0.002). The T-cell frequencies for peptide pools were greater for subjects with active infection than for subjects with nonrecent latent infection for summed RD1 peptide pools (P ≤ 0.006) and culture filtrate protein 10 (CFP-10) antigen (P = 0.029). Individuals with recently acquired (<6 months) versus remotely acquired (>6 months) latent infection did not differ in numbers of peptide pools recognized, proportions recognizing any individual antigen or peptide pool, or antigen-specific T-cell frequencies (P ≥ 0.11). The hierarchy of immunodominance for different antigens was purified protein derivative (PPD) > CFP-10 > early secretory antigenic target 6 > Rv3879c > Rv3878 > Rv3873 > Acr1, and the hierarchies were very similar for active and remotely acquired latent infections. Responses to the DosR antigen {alpha}-crystallin were not associated with latency (P = 0.373). In contrast to the RD1-specific responses, the responses to PPD were not associated with clinical status (P > 0.17) but were strongly associated with positive tuberculin skin test results (≥15-mm induration; P ≤ 0.01). Our results suggest that RD1-specific IFN-{gamma}-secreting T-cell frequencies correlate with the presence of disease rather than with protective immunity in M. tuberculosis-infected individuals and do not distinguish recently acquired asymptomatic infection from remotely acquired latent infection.

* Corresponding author. Mailing address: Tuberculosis Research Unit, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom. Phone: 44 207 594 0883. Fax: 44 207 594 0882. E-mail: a.lalvani{at}imperial.ac.uk

{triangledown} Published ahead of print on 14 September 2009.

Editor: J. L. Flynn

Infection and Immunity, December 2009, p. 5486-5495, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.01436-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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