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Institut National de la Santé et de la Recherche Médicale, Unité 591, Université Paris Descartes, Institut Necker, Paris, France
The role of CD4 help during CD8 memory differentiation has been clearly demonstrated in different experimental models. However, the mechanisms involved to mediate CD4 help and the extent of its effects remain largely unknown. Using gene analysis at a single cell level, which allows the study of gene expression in terms of frequency, intensity and coxpression, we show that unhelped CD8 T cells harbor severe defects in the expression of crucial genes involved in proliferation, survival, and cytotoxic functions, the three main characteristics of CD8 memory differentiation described so far. Importantly, during secondary response, unhelped CD8 T cells exhibit blockade in all cytotoxic pathways (perforin, Fas ligand, IFN-
), demonstrating the highly ubiquitous effect of CD4 help. Secondly, resting unhelped CD8 T cells extinguish the majority of their stimulated genes, showing that CD4 help favors the persistence of gene expression. Indeed, during secondary response, unhelped CD8 T cells exhibit a profile very similar to naive T cells, demonstrating that no instructive program has been imprinted in these cells. Finally unhelped CD8 T cells exhibit a higher sensitivity to immunoregulatory genes during secondary immune response. Therefore, these results characterize the multiple effects of CD4 help on CD8 memory differentiation and provide important insights for the understanding of protective memory responses.
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 the Agence Nationale de la Recherche. L.R. was supported by the Ministére de la Recherche, the Fondation pour la Recherche Médicale, and Association de la Recherche contre le Cancer.
2 Address correspondence and reprint requests to Dr. Corinne Tanchot, Institut National de la Santé et de la Recherche Médicale, Unité 591, Institut Necker, 156 rue de Vaugirard, 75015 Paris, France. E-mail address: tanchot{at}necker.fr
3 Abbreviations used in this paper: Tg, transgenic; LN, lymph node; CD62L, CD62 L-selectin; BM, bone marrow; FasL, Fas ligand.
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