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Dendritic cells, the most powerful antigen-presenting cells, are important for triggering of the immune responses to allo-antigens. However, they also play a fundamental role in the peripheral tolerance maintenance. Tolerance is enhanced by the presence on the dendritic cell surface of the inhibitor receptors ILT3 and ILT4. They recruit protein tyrosine-phosphatases to their ITIM domains and inhibit antigen-presenting cell activation, leading T cell hypo-responsivensess. Moreover, these receptors favor a bidirectional interaction with T-suppressor and T-regulator cells, generating an antigen-specific immunoregulator cascade, in which the dendritic cell behaves as a tolerogenic cell. In the current review, analysis is centered on the biology and behavior of the tolerogenic dendritic cells that express high levels of ILT3 and ILT4. Some molecular and genetics aspects of these receptors are discussed as well as their importance in the modulation of the allo-specific antigen immune response to transplants.

The immune response elicited by an allogenic transplant usually leads to an effector response resulting in allograft rejection; however, some individuals maintain a long-term functioning transplant without signs of rejection (operational tolerance) even in the absence of immunosuppression. It has been suggested that the same mechanisms are responsible for tolerance to self-antigens and alloantigens. One of such mechanisms is immune regulation and several cell subsets with regulatory properties have been identified. Among them, the best characterized cell populations are the regulatory T cells (Treg). Although Treg in mice are CD4+CD25+, in humans the Treg phenotype is restricted to CD4 T cells with high expression of CD25 (CD25high) and Foxp3. Phenotypic and functional analysis of circulating regulatory or suppressor T cells in transplant patients may be useful for detection of operationally tolerant patients. Moreover, future in vitro manipulation of these cells with therapeutic purposes could lead to accomplish induction of in vivo tolerance in clinical transplantation. Herein, we review the experimental and clinical evidence for the role of regulatory cells in transplant biology.

The mechanisms underlying long-term acceptance of kidney allografts in humans under minimal or no maintenance immunosuppression are poorly understood. We analyzed the T-cell receptor (TCR) repertoires in circulating T cells of patients with long-term (> or = 9 years) renal allograft survival with (LTS-IS) and without immunosuppression (LTS-NoIS). T cells of LTS patients exhibited strongly altered TCR Vss usage, including an increased frequency of oligoclonality and a decreased frequency of polyclonality. All 3 LTS-NoIS and 12 of 16 LTS-IS patients demonstrated oligoclonality in at least three or more TCR V beta families, and the frequency of oligoclonality in these patients was significantly higher as compared to patients with well-functioning grafts at 3 years (p < 0.005 both), an uncomplicated course during the first year (p < 0.0001, both), acute rejection (p < 0.0001, both), chronic allograft nephropathy at 7 (p < 0.0001, both) or 13 years (p < 0.0001, both), dialysis patients (p < 0.0001, both) or healthy controls (p < 0.0001, both). In contrast to LTS patients, all other studied patient groups exhibited a polyclonal TCR repertoire. Our data indicate that TCR alteration is a common feature of long-term allograft outcome, which might be explained by clonal deletion, exhaustion of alloreactive T cells or predominant expression of particular T-cell subpopulations, such as regulatory T cells.

Background: Patients with long-term functioning organ allografts may have developed different mechanisms that explain the lack of graft rejection. However, it is not known how these mechanisms interplay or whether one of them predominates in such situations., Methods: The authors analyzed the expression of T-cell surface molecules involved in alloantigen recognition, signal transduction, co-stimulation, and activation markers on circulating T cells from patients with normal kidney function 10 or more years after transplantation, short-term survival (1-4 years), and chronic rejection and from healthy adults. The percentage and the median fluorescent intensity of each marker were determined by flow cytometry. Proliferative response against specific and third-party donors and mitogenic stimulation were also determined., Results: Peripheral blood lymphocytes from patients with long-term surviving kidneys had decreased expression of T-cell receptor (TCR)-alphabeta (P < 0.01), CD3epsilon (P < 0.05), and CD3 zeta-chains (P < 0.001); diminished percentages of CD4(+)CD28(+) (P < 0.001) cells; and increased expression of CTLA-4(+) (P < 0.01) on CD3(+) cells. CD4(+)CD25(+)CD69(+) cells were also increased in long-term surviving patients. Long-term surviving patients had decreased donor-specific proliferative responses., Conclusions: The decreased expression of TCR-alphabeta and epsilon- and zeta-chains on circulating T cells of long-term surviving patients suggests that these cells may have defects in alloantigen recognition or signal transduction that may result in decreased numbers of T cells expressing co-stimulatory molecules and activation markers as well as a decreased specific proliferative response. The decrease in the percentage of CD28(+) cells and the increase in CD4(+)CD25(+)CD69(+) cells suggest that regulatory mechanisms of the immune response are still active in such patients.