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Manipulating the Rate of Memory CD8⁺ T Cell Generation after Acute Infection¹

Vladimir P. Badovinac^* and John T. Harty^2,*,

^* Department of Microbiology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242

Infection with Listeria monocytogenes elicits expansion in numbers of Ag-specific CD8⁺ T cells, which then undergo programmed contraction. The remaining cells undergo further phenotypic and functional changes with time, eventually attaining the qualities of memory CD8⁺ T cells. In this study, we show that L. monocytogenes-specific CD8⁺ T cell populations primed in antibiotic-pretreated mice undergo brief effector phase, but rapidly develop phenotypic (CD127^high, CD43^low) and functional (granzyme B^low, IL-2-producing) characteristics of memory CD8⁺ T cells. These early memory CD8⁺ T cells were capable of substantial secondary expansion in response to booster challenge at day 7 postinfection, resulting in significantly elevated numbers of secondary effector and memory CD8⁺ T cells and enhanced protective immunity compared with control-infected mice. Although early expansion in numbers is similar after L. monocytogenes infection of antibiotic-pretreated and control mice, the absence of sustained proliferation coupled with decreased killer cell lectin-like receptor G-1 up-regulation on responding CD8⁺ T cells may explain the rapid effector to memory CD8⁺ T cell transition. In addition, antibiotic treatment 2 days post-L. monocytogenes challenge accelerated the generation of CD8⁺ T cells with memory phenotype and function, and this accelerated memory generation was reversed in the presence of CpG-induced inflammation. Together, these data show that the rate at which Ag-specific CD8⁺ T cell populations acquire memory characteristics after infection is not fixed, but rather can be manipulated by limiting inflammation that will in turn modulate the timing and extent to which CD8⁺ T cells proliferate and up-regulate killer cell lectin-like receptor G-1 expression.

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 Grants ROIAI42767, ROIAI46653, ROIAI50073, ROIAI059752, and POIAI60699 (to J.T.H.), and by American Cancer Society Grant administered through The Holden Comprehensive Cancer Center at the University of Iowa (IRG-77-004-28) (to V.P.B.).

² Address correspondence and reprint requests to Dr. John T. Harty, Department of Microbiology, University of Iowa, 3-512 Bowen Science Building, 51 Newton Road, Iowa City, IA 52242. E-mail address: john-harty{at}uiowa.edu

³ Abbreviations used in this paper: DC, dendritic cell; Amp, ampicillin; int, intermediate; KLRG-1, killer cell lectin-like receptor G-1; LCMV, lymphocytic choriomeningitis virus; LLO, listeriolysin O; NP, nucleoprotein; ODN, oligodeoxynucleotide; Tg, transgenic.

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