Why T Cells of Thymic Versus Extrathymic Origin Are Functionally Different

Abstract

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-γ. IFN-γ up-regulates Fas and FasL on extrathymic CD8 T cells, thereby leading to their demise by Fas-mediated apoptosis. Moreover, IFN-γ and probably IL-2 curtail survival of extrathymic CD4 T cells by down-regulating IL-7Rα 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.

Development and Function of Innate Polyclonal TCRαβ+ CD8+ Thymocytes

“…Approximately 10% of CD8 SP thymocytes were innate T cells. They differed in many respects from conventional CD8 thymocytes and were similar to innate CD8 T cells generated extrathymically (9,10) or in the thymus of mutant mice (4,8). Based on two criteria, the amount of sjTRECs and the concentration of RAG2p-dependent GFP, innate and conventional CD8 thymocytes had undergone the same number of cell divisions after rearrangement of their TCRa-chains.…”

“…Studies in oncostatin M-transgenic mice infected with lymphocytic choriomeningitis virus have allowed us to evaluate the protective value of innate T cells in the absence of conventional T cells (66). In this model, innate CD8 T cells could not substitute for conventional T cells in providing long-term control of infection, because they underwent proliferative exhaustion and apoptosis (10,67). Nevertheless, innate CD8 T cells initiated proliferation swiftly, secreted copious amounts of IFN-g, and were able to provide initial control of lymphocytic choriomeningitis virus infection.…”

“…Such innate CD8 + T cells are present in large numbers in two settings. First, the abundant extrathymic CD8 + T cells produced in the lymph nodes of oncostatin M-transgenic mice are innate T cells (9,10). Second, innate T cells represent a large proportion of CD4…”

Immunoproteasomes Shape the Transcriptome and Regulate the Function of Dendritic Cells

“…Flow cytometry analyses were done on a BD LSR II flow cytometer using FACSDiva (BD Biosciences) and FCS v.3.0 (De Novo Software) softwares. To calculate the frequency of responding OT-1 T cells, division peaks (as determined by CFSE intensity) were labeled from 0 to n. Making use of the experimentally determined number of events under each CFSE fluorescence peak, the absolute and the relative frequency of OT-1 precursors that responded to SIINFEKL-pulsed DCs was calculated as previously described (25,26): the sum of the extrapolated responding precursors for division cycles from 1 to n allowed us to determine the relative or the absolute size of the precursor sample pool that responded.…”

Immunohistochemical evidences showing the presence of thymulin containing cells located in involuted thymus and in peripheral lymphoid organs

“…These findings almost perfectly match with the fact that the serum level of thymulin increases in this disease (Incefy et al, 1980), giving a possible explanation for the characteristic excessive T cell proliferation. A second possible role of thymulin generated outside of thymus may be its contribution to the extrathymic T cell generation pathway that has been postulated for many years (MacDonald et al, 1981;Lawetsky et al, 1988 ) and we know now that it exists (Lake et al, 1991), giving rise to a definitive T cell population with different attributes compared to the one generated in the classical thymic pathway (Blais et al, 2008).…”