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Dynamic Relationship between IFN- and IL-2 Profile of Mycobacterium tuberculosis-Specific T Cells and Antigen Load¹

Kerry A. Millington^*,, John A. Innes, Sarah Hackforth, Timothy S. C. Hinks, Jonathan J. Deeks, Davinder P. S. Dosanjh, Valerie Guyot-Revol, Rubamalaar Gunatheesan, Paul Klenerman^¶ and Ajit Lalvani^2,*,

^* Tuberculosis Immunology Group, Department of Respiratory Medicine, National Heart and Lung Institute, Wright Fleming Institute of Infection and Immunity, Imperial College London, London, United Kingdom; Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; Department of Infection and Tropical Medicine, Birmingham Heartlands Hospital, Birmingham, United Kingdom; Department of Public Health and Epidemiology University of Birmingham, Birmingham, United Kingdom; and ^¶ Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom

Distinct IFN- and IL-2 profiles of Ag-specific CD4⁺ T cells have recently been associated with different clinical disease states and Ag loads in viral infections. We assessed the kinetics and functional profile of Mycobacterium tuberculosis Ag-specific T cells secreting IFN- and IL-2 in 23 patients with untreated active tuberculosis when bacterial and Ag loads are high and after curative treatment, when Ag load is reduced. The frequencies of M. tuberculosis Ag-specific IFN--secreting T cells declined during 28 mo of follow-up with an average percentage decline of 5.8% per year (p = 0.005), while the frequencies of Ag-specific IL-2-secreting T cells increased during treatment (p = 0.02). These contrasting dynamics for the two cytokines led to a progressive convergence of the frequencies of IFN-- and IL-2-secreting cells over 28 mo. Simultaneous measurement of IFN- and IL-2 secretion at the single-cell level revealed a codominance of IFN--only secreting and IFN-/IL-2 dual secreting CD4⁺ T cells in active disease that shifted to dominance of IFN-/IL-2-secreting CD4⁺ T cells and newly detectable IL-2-only secreting CD4⁺ T cells during and after treatment. These distinct T cell functional signatures before and after treatment suggest a novel immunological marker of mycobacterial load and clinical status in tuberculosis that now requires validation in larger prospective studies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by the Wellcome Trust. K.A.M. is supported by a Wellcome Trust Ph.D. Prize Studentship. P.K. and A.L. are Wellcome Senior Research Fellows in Clinical Science. P.K. is also supported by the James Martin School, University of Oxford. J.J.D. is supported by a Department of Health Senior Fellowship in Evidence Synthesis, and D.P.S.D. is supported by the Sir Halley Stewart Trust.

² Address correspondence and reprint requests to Prof. Ajit Lalvani, Tuberculosis Immunology Group, Department of Respiratory Medicine, National Heart and Lung Institute, Wright Fleming Institute of Infection and Immunity, Imperial College London, Norfolk Place, London W2 1PG, U.K. E-mail address: a.lalvani{at}imperial.ac.uk

³ Abbreviations used in this paper: T_EM, effector memory T cell; BCG, bacille Calmette-Guérin; CFP-10, culture filtrate protein; CI, confidence interval; ESAT-6, early secreted antigenic target protein; PPD, purified protein derivative; SFC, spot-forming cell; SKSD, streptokinase streptodornase; T_CM, central memory T cell; TST, tuberculin skin test.

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