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Increasing the CD4⁺ T Cell Precursor Frequency Leads to Competition for IFN- Thereby Degrading Memory Cell Quantity and Quality¹

Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA 92037

The precursor frequency of naive CD4⁺ T cells shows an inverse relationship with the number of memory cells generated after exposure to cognate Ag. Using the lymphocytic choriomeningitis virus (LCMV) model, we show here that only when the initial number of naive virus-specific CD4⁺ T cell precursors is low (10⁴ per spleen) do they give rise to abundant and homogeneous memory cells that are CD62L^low, IL-7R^high, and imbued with an enhanced capacity to produce cytokine, proliferate, and survive over time. Furthermore, memory cells derived from a high naive precursor number show functional deficits upon secondary exposure to virus. The negative effect of higher naive precursor frequency was not attributable to competition for limiting amounts of Ag, because LCMV-naive CD4⁺ TCR-transgenic CD4 T cells were recruited into the LCMV-induced response even when their initial number was high. Instead, the T cells appear to compete for direct IFN- signals as they differentiate into memory cells. These results are consistent with a model of T cell development in which the most fit effector T cells that receive sufficient direct IFN- signals are selected to differentiate further into memory 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 R-01 Grants AI-052351 and AI-077607 (to J.L.W.).

² Address correspondence and reprint requests to Dr. J. Lindsay Whitton, Molecular and Integrative Neurosciences Department, SP30-2110, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: lwhitton{at}scripps.edu

³ Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; KO, knockout; LM, Listeria monocytogenes.

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