Both CD4+CD25+ and CD4+CD25− Regulatory Cells Mediate Dominant Transplantation Tolerance

Abstract

CD4+CD25+ T cells have been proposed as the principal regulators of both self-tolerance and transplantation tolerance. Although CD4+CD25+ T cells do have a suppressive role in transplantation tolerance, so do CD4+CD25− T cells, although 10-fold less potent. Abs to CTLA-4, CD25, IL-10, and IL-4 were unable to abrogate suppression mediated by tolerant spleen cells so excluding any of these molecules as critical agents of suppression. CD4+CD25+ T cells from naive mice can also prevent rejection despite the lack of any previous experience of donor alloantigens. However, this requires many more naive than tolerized cells to provide the same degree of suppression. This suggests that a capacity to regulate transplant rejection pre-exists in naive mice, and may be amplified in “tolerized” mice. Serial analysis of gene expression confirmed that cells sorted into CD4+CD25+ and CD4+CD25− populations were distinct in that they responded to TCR ligation with very different programs of gene expression. Further characterization of the differentially expressed genes may lead to the development of diagnostic tests to monitor the tolerant state.

Expression Profiling of Murine Double-Negative Regulatory T Cells Suggest Mechanisms for Prolonged Cardiac Allograft Survival

“…Many types of Treg cells are known to be present in various animal and human disease models. The most extensively studied Treg cell populations are CD4 ϩ , which include CD4 ϩ CD25 ϩ cells (7), Tr1 cells (8), CD4 ϩ CD103 ϩ T cells (9), and CD4 ϩ CD25 Ϫ Treg cells (10). In addition to CD4 ϩ T cells, CD8 ϩ CD28 Ϫ cells (11), ␥␦ T cells (12), NK T cells (13), and ␣␤TCR ϩ CD3 ϩ NK1.1 Ϫ CD4 Ϫ CD8 Ϫ double-negative (DN) T cells (14 -18) have also been shown to have potent immunoregulatory function.…”

“…Recently, several groups have used this approach in an attempt to identify specific markers for CD4 ϩ CD25 ϩ Treg cells. By comparing CD4 ϩ CD25 ϩ Tr cells to CD4 ϩ CD25 Ϫ T cells (9,10,22,23), it was discovered that CD4 ϩ CD25 ϩ Treg cells have a unique expression profile of various genes, including suppressors of cytokine signaling and glucocorticoid-induced TNFR family-related receptor, a member of the TNFR superfamily (22). Furthermore, differences in the regulation of apoptosis, cell cycle, cytokine receptor, cell-cell interaction, and stress pathway genes were also observed (23).…”

Development of CD25– regulatory T cells following heart transplantation: Evidence for transfer of long‐term survival

“…However, previous studies from our laboratory have shown that a roughly similar quantity of purified CD4 + CD25 + T cells from desoxyspergualine derivate-treated animals was highly efficient in transferring tolerance in the same strain combination, suggesting that different mechanisms operate in different tolerance induction models, even in the same genetic background [29]. Regulatory CD25 -T cells derived from induced regulatory CD25 + T cells have been suggested by other studies [46][47][48][49]. These studies have shown that CD25 -T cells with regulatory function originally derived from CD25 + precursors [49] and that CD25 expression may not always be a stable marker for regulatory T cells in the periphery [49].…”

“…These studies have shown that CD25 -T cells with regulatory function originally derived from CD25 + precursors [49] and that CD25 expression may not always be a stable marker for regulatory T cells in the periphery [49]. The CD25 -T cell population also prevented the rejection of a skin graft between minor MHC mismatch mice only if derived from tolerant mice, but not from naive ones [47]. Similarly, in our model, CD25 -T cells exhibited in vitro regulatory functions only when derived from tolerant animals and not from naive animals.…”

Gene Therapy Progress and Prospects: Gene therapy in organ transplantation

“…These regulatory cells can be induced using a variety of approaches including administration of nondepleting anti-CD4 antibodies and exposure to a tolerizing antigen in the form of donor-specific transfusions. [21][22][23] Often regulatory cells are able to induce tolerance to both the tolerizing antigen and third-party antigens, as long as they are both expressed on the same graft, suggesting that inhibition occurs locally. 21,22 Recently, it has been shown that treatment of immunocompetent mice with nondepleting anti-T-cell antibodies together with syngeneic bone marrow infected with adenoviruses carrying an allogeneic MHC class I gene can lead to the acceptance of fully-allogeneic cardiac transplants which share the same MHC class I antigen carried by the adenovirus construct.…”