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* Institute for Research in Immunology and Cancer and
Department of Medicine, University of Montréal;
Centre de Recherche du Centre Hospitalier de l’Université de Montréal; and
Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada
Age-related thymic involution severely impairs immune responsiveness. Strategies to generate T cells extrathymically are therefore being explored with intense interest. We have demonstrated that T cells produced extrathymically were functionally deficient relative to thymus-derived T cells. The main limitation of extrathymic T cells is their undue susceptibility to apoptosis; they thus do not expand properly when confronted with pathogens. Using oncostatin M-transgenic mice, we found that in the absence of lymphopenia, T cells of extrathymic origin constitutively undergo excessive homeostatic proliferation that leads to overproduction of IL-2 and IFN-
. IFN- up-regulates Fas and FasL on extrathymic CD8 T cells, thereby leading to their demise by Fas-mediated apoptosis. Moreover, IFN- and probably IL-2 curtail survival of extrathymic CD4 T cells by down-regulating IL-7R
and Bcl-2, and they support a dramatic accumulation of FoxP3+ T regulatory cells. Additionally, we show that wild-type thymus-derived T cells undergoing homeostatic proliferation in a lymphopenic host shared key features of extrathymic T cells. Our work explains how excessive lymphopenia-independent homeostatic proliferation renders extrathymic T cells functionally defective. Based on previous work and data presented herein, we propose that extrathymic T cells undergo constitutive homeostatic proliferation because they are positively selected by lymph node hemopoietic cells rather than by thymic epithelial 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 the Canadian Institutes of Health Research (Grant MOP 42384). M.E.B. and M.G. are supported by training grants from the National Cancer Institute of Canada and the Cole Foundation, respectively. C.P. and R.P.S. hold Canada Research Chairs in Immunobiology and in Human Immunology, respectively.
2 Address correspondence and reprint requests to Dr. Claude Perreault, Institute for Research in Immunology and Cancer, P.O. Box 6128, Station Centre-Ville, Montreal, Québec H3C 3J7, Canada. E-mail address: c.perreault{at}videotron.ca
3 Abbreviations used in this paper: LN, lymph node; FasL, Fas ligand; GMFI, geometric MFI; HP, homeostatic proliferation; LCMV, lymphocytic choriomeningitis virus; OM, oncostatin M; qPCR, quantitative real-time PCR; TREC, TCR excision circle; Treg cell, regulatory T cell; WT, wild type.
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