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Homeostasis and Effector Function of Lymphopenia-Induced "Memory-Like" T Cells in Constitutively T Cell-Depleted Mice¹

David Voehringer^2,*,, Hong-Erh Liang^* and Richard M. Locksley^2,*

^* Howard Hughes Medical Institute, Department of Medicine, University of California, San Francisco, CA 94143; and Institute for Immunology, University of Munich, Munich, Germany

Naive T lymphocytes acquire a phenotype similar to Ag-experienced memory T cells as a result of proliferation under lymphopenic conditions. Such "memory-like" T (T_ML) cells constitute a large fraction of the peripheral T cell pool in patients recovering from T cell ablative therapies, HIV patients under highly active antiretroviral therapy, and in the elderly population. To generate a model that allows characterization of T_ML cells without adoptive transfer, irradiation, or thymectomy, we developed genetically modified mice that express diphtheria toxin A under control of a loxP-flanked stop cassette (R-DTA mice). Crossing these mice to CD4Cre mice resulted in efficient ablation of CD4 single-positive thymocytes, whereas double-positive and CD8 single-positive thymocytes were only partially affected. In the periphery the pool of naive (CD44^lowCD62L^high) T cells was depleted. However, some T cells were resistant to Cre activity, escaped deletion in the thymus, and underwent lymphopenia-induced proliferation resulting in a pool of T_ML cells that was similar in size and turnover to the pool of CD44^highCD62L^low "memory phenotype" T cells in control mice. CD4Cre/R-DTA mice remained lymphopenic despite the large available immunological "space" and normal Ag-induced T cell proliferation. CD4Cre/R-DTA mice showed a biased TCR repertoire indicating oligoclonal T cell expansion. Infection with the helminth Nippostrongylus brasiliensis resulted in diminished effector cell recruitment and impaired worm expulsion, demonstrating that T_ML cells are not sufficient to mediate an effective immune response.

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 in part by National Institutes of Health Grant AI30663 and the Howard Hughes Medical Institute, the Sandler Asthma Basic Research Center (to R.M.L.), and the Emmy Noether Program of the Deutsche Forschungsgemeinschaft (grant Vo944/2 to D.V.).

² Address correspondence and reprint requests to Dr. R. M. Locksley, University of California, Box 0654, S 1032B, 513 Parnassus Avenue, San Francisco, CA 94143. E-mail address: locksley{at}medicine.ucsf.edu or Dr. David Voehringer, Institute for Immunology, University of Munich, Goethestrasse 31, Munich, D-80336 Germany. E-mail address: david.voehringer{at}med.uni-muenchen.de

³ Abbreviations used in this paper: T_MP, "memory phenotype" T; T_ML, "memory-like" T; DTA, diphtheria toxin A; Hprt, hypoxanthine phosphoribosyltransferase; DN, double negative; DP, double positive; SP, single positive; Treg, regulatory T; KLRG1, killer cell lectin-like receptor G1; Siglec, sialic acid-binding Ig-like lectin.