Do thymically and strictly extrathymically developing T cells generate similar immune responses?

Abstract

IntroductionOne hallmark of the adaptive immune system is that the thymus has been conserved as the primary T-lymphoid organ during 450 million years of evolution. 1 This level of conservation is remarkable when one considers that about 10 different organs have been used as primary sites of hematopoiesis in jawed vertebrates. 1 Thymic epithelial cells (TECs) derived from the third pharyngeal pouch are the main constituent of the thymic environment. 2 TECs provide 2 types of signals to thymocytes: T-cell receptor (TCR)-dependent and TCR-independent. [3][4][5] In conjunction with mesenchymal cells, TECs have a unique ability to provide TCR-independent interactions that are essential for several thymocyte developmental events but whose nature is still elusive. 2,[6][7][8][9] Indeed, studies in wild-type and TCR-transgenic euthymic and nude mice indicated that the efficiency of generating mature T cells was 100 to 1000 times less in nude compared to euthymic mice. 5 In contrast, TCR-mediated signals, dictating which TCR clonotypes are positively selected, can be supported by major histocompatibility complex (MHC)-peptide complexes displayed by other cell types. Thus, studies involving hematopoietic chimeras and thymus grafts have shown that hematopoietic cells can mediate positive selection of CD8 T cells in vivo. 5,10,11 In line with this, studies in tetraparental aggregation chimeras have demonstrated that the MHC of TECs is not required for efficient positive selection of MHC Ia-and MHC II-restricted T cells. 12 Moreover, under normal circumstances, preferential or exclusive positive selection on hematopoietic cells appears to be a general characteristic shared by many (if not all) MHC class Ib-restricted T cells. [13][14][15] These data indicate that the nonredundant role of TECs is to provide TCR-independent signals to thymocytes, but that TCR signals can be provided by other cells in the thymus and the periphery. 5,16 These considerations raise the question of whether the canonical influence of TECs on T-cell development is essential for survival. Would lymphocytes developing in a TEC-free milieu be functional and reach sufficient numbers to eradicate pathogens? Oncostatin M (OM)-transgenic mice represent a unique model to directly address this issue. Remarkably, chronic exposure to OM transforms the lymph node (LN) into a "primary" lymphoid organ whose ability to support T-cell development and to seed secondary lymphoid organs is similar to that of a normal thymus. 17,18 The lymphopoietic pathway modulated by OM is truly thymusindependent and takes place only in the LNs. 17,18 The proportions of double-negative, double-positive, and single-positive T cells in the OM ϩ LNs reproduce those found in a thymus, and the TCR repertoire of the single-positive cells is diversified. The effect of OM on extrathymic T-cell development in the LNs is probably due to some amplification of a cryptic pathway that is operative in conditions of defective thymopoiesis and was nicely characterized in nude mice. 19 Like normal LNs...

The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation

“…50 Extrathymic de novo generation of donor T cells observed in our studies may also provide some protection from MCMV infection, 50 despite their lower number and poorer function compared with thymic-derived T cells. 11,51 In summary, our findings offer new insights into the contribution of Tregs in maintaining an optimal microenvironment for the reconstitution of functional immunity. Protection of the thymic and nodal niches in which T-cell generation and homeostasis occur is a major mechanism by which Tregs mediate their protective effects, and may help explain the intrinsic link between the suppression of GvHD and an enhancement of immune reconstitution following adoptive transfer of Tregs.…”

Total loss of HLA class I expression on a melanoma cell line after growth in nude mice in absence of autologous antitumor immune response

“…These AndoNude cells might have appeared by an immunoselection of rare HLA-negative cells, in which extrathymic T lymphocytes present in nude mice might have been implicated, 20,21 although it has been shown that these extrathymic T lymphocytes cannot functionally substitute classic thymic T cells. 22 It is also possible that NK cells present in nude mice might xenogenically recognise Ando-2 melanoma cells and produce immunoselection of AndoNude melanoma cells. However, SCID-Beige mice have neither T lymphocytes nor NK cells, and Ando-2 melanoma cells presented a strong HLA class I down-regulation after their passage in these mice.…”

Development and Function of Innate Polyclonal TCRαβ+ CD8+ Thymocytes

“…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.…”