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Antigen-Specific CD8⁺ T Cells and the Development of Central Memory during Mycobacterium tuberculosis Infection¹

Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115

Whether true memory T cells develop in the face of chronic infection such as tuberculosis remains controversial. To address this question, we studied CD8⁺ T cells specific for the Mycobacterium tuberculosis ESAT6-related Ags TB10.3 and TB10.4. The shared epitope TB10.3/10.4_20–28 is presented by H-2 K^d, and 20–30% of the CD8⁺ T cells in the lungs of chronically infected mice are specific for this Ag following respiratory infection with M. tuberculosis. These TB10.3/10.4_20–28-specific CD8⁺ T cells produce IFN- and TNF and express CD107 on their cell surface, which indicates their likely role as CTL in vivo. Nearly all of the Ag-specific CD8⁺ T cells in the lungs of chronically infected mice had a T effector cell phenotype based on their low expression of CD62L and CD45RB. In contrast, a population of TB10.3/10.4_20–28-specific CD8⁺ T cells was identified in the lymphoid organs that express high levels of CD62L and CD45RB. Antibiotic treatment to resolve the infection led to a contraction of the Ag-specific CD8⁺ T cell population and was accompanied by an increase in the proportion of CD8⁺ T cells with a central memory phenotype. Finally, challenge of memory-immune mice with M. tuberculosis was accompanied by significant expansion of TB10.3/10.4_20–28-specific CD8⁺ T cells, which suggests that these cells are in fact functional memory T cells.

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 supported by National Institutes of Health Grant R01 AI47171, AI067731, and an American Lung Association Career Investigator Award (to S.M.B.).

² A.K. and J.S.M.W. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Samuel M. Behar, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Smith Building Room 516C, One Jimmy Fund Way, Boston, MA 02115. E-mail address: sbehar{at}rics.bwh.harvard.edu

⁴ Abbreviations used in this paper: BCG, bacillus Calmette-Guérin; A488, alexa488; BAL, bronchoalveolar lavage; INH, isoniazid; LN, lymph node; MNC, mononuclear cell; PLN, pulmonary LN; T_CM, central memory T cell.

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