| First Author | Blais ME | Year | 2008 |
| Journal | J Immunol | Volume | 180 |
| Issue | 4 | Pages | 2299-312 |
| PubMed ID | 18250439 | Mgi Jnum | J:131997 |
| Mgi Id | MGI:3774916 | Doi | 10.4049/jimmunol.180.4.2299 |
| Citation | Blais ME, et al. (2008) Why T cells of thymic versus extrathymic origin are functionally different. J Immunol 180(4):2299-312 |
| abstractText | 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. |
