Immune regulation by regulatory T cells: implications for transplantation (original) (raw)
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Immunological Reviews, 2003
Transplantation tolerance can be induced in adult rodents using monoclonal antibodies against coreceptor or costimulation molecules on the surface of T cells. There are currently two wellcharacterized populations of T cells, demonstrating regulatory capacity: the 'natural' CD4 þ CD25 þ T cells and the interleukin (IL)-10-producing Tr1 cells. Although both types of regulatory T cells can induce transplantation tolerance under appropriate conditions, it is not clear whether either one plays any role in drug-induced dominant tolerance, primarily due to a lack of clear-cut molecular or functional markers. Similarly, although dendritic cells (DCs) can be pharmacologically manipulated to promote tolerance, the phenotype of such populations remains poorly defined. We have used serial analysis of gene expression (SAGE) with 29 different T-cell and antigen-presenting cell libraries to identify gene-expression signatures associated with immune regulation. We found that independently derived, regulatory Tr1-like clones were highly concordant in their patterns of gene expression but were quite distinct from CD4 þ CD25 þ regulatory T cells from the spleen. DCs that were treated with the tolerance-enhancing agents IL-10 or vitamin D3 expressed a gene signature reflecting a functional specification in common with the most immature DCs derived from embryonic stem cells.
Dendritic cells, T cell tolerance and therapy of adverse immune reactions
Clinical & …, 2003
Dendritic cells (DC) are uniquely able to either induce immune responses or to maintain the state of self tolerance. Recent evidence has shown that the ability of DC to induce tolerance in the steady state is critical to the prevention of the autoimmune response. Likewise, DC have been shown to induce several type of regulatory T cells including Th2, Tr1, Ts and NKT cells, depending on the maturation state of the DC and the local microenvironment. DC have been shown to have therapeutic value in models of allograft rejection and autoimmunity, although no success has been reported in allergy. Several strategies, including the use of specific DC subsets, genetic modification of DC and the use of DC at various maturation stages for the treatment of allograft rejection and autoimmune disease are discussed. The challenge for the future use of DC therapy in human disease is to identify the appropriate DC for the proposed therapy; a task made more daunting by the extreme plasticity of DC that has recently been demonstrated. However, the progress achieved to date suggests that these are not insurmountable obstacles and that DC may become a useful therapeutic tool in transplantation and autoimmune disease. Keywords dendritic cells tolerance T cells transplantation autoimmunity allergy DENDRITIC CELLS: CRITICAL REGULATORS OF IMMUNITY Dendritic leukocytes are rare (< 1% of circulating blood mononuclear cells) heterogeneous, uniquely well-equipped bone marrow
Tolerogenic Dendritic Cell-Regulatory T-cell Interaction and the Promotion of Transplant Tolerance
Transplantation, 2009
Evidence has accumulated that targeting of donor alloantigen to quiescent dendritic cells (DC) in situ or adoptive DC therapy is associated with the expansion or induction of regulatory T cells (T reg) in experimental organ transplantation. These Treg can mediate suppression of anti-donor T effector cell responses and promote allograft tolerance. In addition, Treg can exert reciprocal, inhibitory effects on DC that maintain their tolerogenic properties. Several groups have exploited DC to expand alloAg-specific Treg in vitro, followed by adoptive transfer of the Treg to graft recipients, an approach that holds promise for tolerogenic cell therapy in clinical cell and organ transplantation.
Journal of Leukocyte Biology, 2007
Dendritic cells (DC), professional antigen-presenting cells of the immune system, exert important functions both in induction of T cell immunity, as well as tolerance. It is well established that the main function of immature DC (iDC) in their in vivo steady-state condition is to maintain peripheral tolerance to self-antigens and that these iDC mature upon encounter of so-called danger signals and subsequently promote T cell immunity. Previously, it was believed that T cell unresponsiveness induced after stimulation with iDC is caused by the absence of inflammatory signals in steady-state in vivo conditions and by the low expression levels of costimulatory molecules on iDC. However, a growing body of evidence now indicates that iDC can also actively maintain peripheral T cell tolerance by the induction and/or stimulation of regulatory T cell populations. Moreover, several reports indicate that traditional DC maturation can no longer be used to distinguish tolerogenic and immunogenic properties of DC. This review will focus on the complementary role of dendritic cells in inducing both tolerance and immunity, and we will discuss the clinical implications for dendritic cell-based therapies. J. Leukoc. Biol. 82: 1365-1374; 2007.
Regulatory T cells in the induction and maintenance of peripheral transplantation tolerance
Transplant International, 2003
It is now possible to induce donor-specific transplantation tolerance in adult rodents using non-depleting monoclonal antibodies against T cell co-receptor and costimulation molecules or by immunisation with tolerogenic antigenpresenting cells. It is a common finding of all these models of peripheral tolerance, as well as of various mouse models of autoimmune disease, that regulatory CD4+ T cells are the principal mediators. There are currently no specific markers for regulatory T cells, but in some autoimmune models their activity has been associated with the expression of activation markers
The Journal of Immunology, 2007
Transplants tolerated through a process known as infectious tolerance evoke continuous recruitment of regulatory T (Treg) cells that are necessary to maintain the unresponsive state. This state is maintained long-term and requires continuous Ag exposure. It is not known, however, whether infectious tolerance operates through sustained recruitment of pre-existing regulatory cells, induction of regulatory cells, or both. Using mice deficient in natural Treg cells, we show here that quiescent donor dendritic cells (DC) laden with histocompatibility Ag can induce Treg cells de novo that mediate transplantation tolerance. In contrast, fully activated DC fail to do so. These findings suggest that DC incapable of delivering full activation signals to naive T cells may favor their polarization toward a regulatory phenotype. Furthermore, they suggest a role for quiescent endogenous DC in the maintenance of the tolerant state. The Journal of Immunology, 2007, 179: 967-976.