Why T cells of thymic versus extrathymic origin are functionally different.
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-gamma. IFN-gamma up-regulates Fas and FasL on extrathymic CD8 T cells, thereby leading to their demise by Fas-mediated apoptosis. Moreover, IFN-gamma and probably IL-2 curtail survival of extrathymic CD4 T cells by down-regulating IL-7Ralpha 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.
Blais
Marie-Eve
ME
Institute for Research in Immunology and Cancer, and Department of Medicine, University of Montreal, Station Centre-Ville, Montreal, Quebec, Canada.
Brochu
Sylvie
S
Giroux
Martin
M
Bélanger
Marie-Pier
MP
Dulude
Gaël
G
Sékaly
Rafick-Pierre
RP
Perreault
Claude
C
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002417:Cattle; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053683:Oncostatin M / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology* / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology*
D019253:Proto-Oncogene Proteins c-bcl-2; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D053683:Oncostatin M