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CD27^low CD4 T Lymphocytes That Accumulate in the Mouse Lungs during Mycobacterial Infection Differentiate from CD27^high Precursors In Situ, Produce IFN-, and Protect the Host against Tuberculosis Infection¹

Marina A. Kapina^2,*, Galina S. Shepelkova^2,*, Vladimir V. Mischenko^*, Peter Sayles, Polina Bogacheva^*, Gary Winslow, Alexander S. Apt^* and Irina V. Lyadova^3,*

^* Department of Immunology, Central Institute for Tuberculosis of the Russian Academy of Medical Sciences, Moscow, Russia; Trudeau Institute, Saranac Lake, NY 12983; and Wadsworth Center, New York State Department of Health, Albany, NY 12201

The generation of effector, IFN- producing T lymphocytes and their accumulation at sites of infection are critical for host protection against various infectious diseases. The activation and differentiation of naive T lymphocytes into effector memory cells starts in lymphoid tissues, but it is not clear whether the Ag-experienced cells that leave lymph nodes (LN) are mature or if they undergo further changes in the periphery. We have previously shown that CD44^highCD62L^low effector CD4 T lymphocytes generated during the course of mycobacterial infection can be segregated into two subsets on the basis of CD27 receptor expression. Only the CD27^low subset exhibited a high capacity for IFN- secretion, indicating that low CD27 expression is characteristic of fully differentiated effector CD4 T lymphocytes. We demonstrate now that CD27^low IFN--producing CD4 T lymphocytes accumulate in the lungs but are rare in LNs. Several factors contribute to their preferential accumulation. First, CD27^low CD4 T lymphocytes present in the LN are highly susceptible to apoptosis. Second, circulating CD27^low CD4 T cells do not enter the LN but efficiently migrate to the lungs. Third, CD27^high effector CD4 T cells that enter the lungs down-regulate CD27 expression in situ. In genetically heterogeneous mice that exhibit varying susceptibility to tuberculosis, the accumulation of mature CD27^low CD4 T cells in the lungs correlates with the degree of protection against infection. Thus, we propose that terminal maturation of effector CD4 T lymphocytes in the periphery provides the host with efficient local defense and avoids potentially harmful actions of inflammatory cytokines in lymphoid organs.

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 Russian Foundation for Basic Research Grant 04-04-49396 (to I.V.L.), U.S. Civilian Research and Development Foundation Grant RUB1-2706-MO-07, (to G.W. and I.V.L.), and, in part, by National Institutes of Health Grant 1-RO1-HL68532-01 (to A.S.A.).

² M.A.K. and G.S.S. contributed equally to the work.

³ Address correspondence and reprint requests to Dr. Irina Lyadova, Central Institute for Tuberculosis, Yauza Alley, 2, Moscow 107564, Russia. E-mail address: ivlyadova{at}mail.ru

⁴ Abbreviations used in this paper: TB, tuberculosis; LN, lymph node; BLN, brachial lymph node; i.t., intratracheally.

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