T-cell development is under the tight control of thymic microenvironments. Conversely, the integrity of thymic microenvironments depends on the physical presence of developing thymocytes, a ...phenomenon designated as âthymic crosstalkâ. We now show, using three types of immunodeficient mice, i.e. CD3(epsilon) transgenic mice, RAG(null) mice and RAG(null)-bone-marrow-transplanted CD3(epsilon) transgenic mice, that the control point in lymphoid development where triple negative (CD3(â),CD4(â),CD8(â)) thymocytes progress from CD44(+)CD25(â) towards CD44(â)CD25(+), influences the development of epithelial cells, critically inducing the extra, third dimension in the organization of the epithelial cells in the cortex. This tertiary configuration of the thymic epithelium is a typical feature for the thymus, enabling lymphostromal interaction during T-cell development. Crosstalk signals at this control point also induce the formation of thymic nurse cells. Moreover, our data indicate that establishment of a thymic cortex is a prerequisite for the development of the thymic medulla. Thus, differentiating thymocytes regulate the morphogenesis of thymic microenvironments in a stepwise fashion.
Our study demonstrates that binding of complement-opsonized HIV to complement receptor type 1 on human erythrocytes (E) via C3b fragments is followed by a rapid normal human serum-mediated detachment ...of HIV from E. The release was dependent on the presence of factor I indicating a conversion of C3b fragments to iC3b and C3d on the viral surface. This in turn resulted in an efficient binding of opsonized HIV to CR2-expressing B cells, thus facilitating B cell-mediated transmission of HIV to T cells. These data provide a new dynamic view of complement opsonization of HIV, suggesting that association of virus with E might be a transient phenomenon and the factor I-mediated processing of C3b to iC3b and C3d on HIV targets the virus to complement receptor type 2-expressing cells. Thus, factor I in concert with CR1 on E and factor H in serum due to their cofactor activity are likely to be important contributors for the generation of C3d-opsonized infectious HIV reservoirs on follicular dendritic cells and/or B cells in HIV-infected individuals.
Thymic microenvironments, 3-D versus 2-D? van Ewijk, Willem; Wang, BaoPing; Hollander, Georg ...
Seminars in immunology,
02/1999, Letnik:
11, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Lympho-stromal interactions in the thymus crucially de- termine the fate of developing T cells. Epithelial cells, inter- digitating reticular cells, macrophages and fibroblasts all play a role in the ...shaping of the T cell repertoire. Recently published evidence shows that lympho-stromal interaction acts bi-directional. Developing T cell themselves, at different stages of differentiation, control the microarchitecture of thymic microenvironments, a phenomenon designated as `crosstalk'. This paper reviews experiments showing that developing T cells crosstalk to different thymic epithelial cells in a stepwise fashion. In this way, correctly organized thymic microenvironments guarantee normal thymopoiesis.
The microbial products cyclosporin A (CsA), FK506 and rapamycin are potent immunosuppressive agents. The introduction of CsA in the early 1970's significantly improved the outcome of organ and bone ...marrow allograft transplantation and advanced therapeutic options in autoimmune diseases. FK506 appears to have a higher therapeutic index than CsA, and has been used with encouraging results in clinical transplantation trials. FK506 and CsA, although structurally unrelated, appear to target similar signal transduction pathways in hematopoietic cells by inhibiting the action of calcineurin, a serine/threonine phosphatase. A structural analog of FK506, rapamycin, inhibits cellular function by a different molecular mechanism. These agents have advanced our understanding of signal transmission pathways in lymphocyte activation.
The CD3 zeta chain of the TCR plays a pivotal role in the activation of T cell responses toward foreign antigen and in the selection of the T cell repertoire. T lymphocytes from mice deficient in CD3 ...zeta (CD3 zeta/eta-/- mice) express very few cell surface TCR-CD3 complexes, and these animals have poorly developed thymuses which lack single-positive CD8 and CD4 thymocytes. Nevertheless, a substantial number of single-positive CD4+ and CD8+ T lymphocytes are found in peripheral lymphoid organs of CD3 zeta/eta-/- animals. Using double-mutant mice, generated by breeding CD3 zeta/eta-/- mice with others deficient in the expression of either class I or class II MHC molecules, we demonstrate here that positive selection of peripheral CD4+ and CD8+ T lymphocytes can occur in the absence of CD3 zeta/eta molecules. Analysis of the intestinal intra-epithelial lymphocytes from CD3 zeta/eta-/- mice revealed a novel T cell population expressing high levels of an alternative TCR alpha beta, due to the replacement of CD3 zeta by Fc epsilon RI gamma. Developmentally, these cells also depend on class I MHC expression. In contrast, TCR gamma delta/Fc epsilon RI gamma+ T cells develop independently of MHC class I or class II molecules. These experiments demonstrate that the unique subset of intestinal TCR alpha beta/Fc epsilon RI gamma+ lymphocytes is developmentally dependent on MHC expression. The restricted expression of TCR alpha beta/Fc epsilon RI gamma+ cells in the intestinal mucosa (rather than the thymus or lymph nodes) supports the hypothesis that selection of these T cells occurs extrathymically.
PDF
