15-37 Regulatory T cells are involved in alloreactive immune responses.
As in all immune responses, regulatory T cells are thought to have an important immunoregulatory role in the alloreactive immune responses involved in graft rejection. Experiments on the transplantation of allogeneic HSCs in mice have thrown some light on this question. Here, depletion of CD25+ Treg cells in either the recipient or the HSC graft before transplantation accelerated the onset of GVHD and subsequent death. In contrast, supplementing the graft with either fresh or ex vivo expanded Treg cells delayed, or even prevented, death from GVHD, with similar results in early human studies. Also, treatment with a low dose of IL-2, which is thought to preferentially expand Treg cells, has shown positive effects in preventing GVHD. Similar observations have been made in experimental mouse models of solid organ transplantation, where the transfer of either naturally occurring or induced Treg cells significantly delayed allograft rejection. These experiments suggest that enriching or generating Treg cells in preparations of donor HSCs might provide a possible therapy for GVHD in the future.
Another class of regulatory T cells, CD8+CD28– T cells, have an anergic phenotype and are thought to maintain T-cell tolerance indirectly by inhibiting the capacity of antigen-presenting cells to activate CD4+ T cells. These cells have been isolated from transplant patients, and can be distinguished from alloreactive CD8 T cells because they do not display cytotoxic activity against donor cells and express high levels of the inhibitory killer receptor CD94 (see Section 3-25). This suggests that CD8+CD28– T cells interfere with the activation of antigen-presenting cells and have a role in the maintenance of transplant tolerance.
15-38 The fetus is an allograft that is tolerated repeatedly.
All of the transplants discussed so far are the result of advances in modern medicine. However, one ‘foreign’ tissue that is repeatedly grafted and tolerated is the mammalian fetus. The fetus carries paternal MHC and minor histocompatibility antigens that differ from those of the mother (Fig. 15.56), and yet a mother can successfully bear many children expressing the same nonself proteins derived from the father. The mysterious lack of fetal rejection has consistently puzzled immunologists, and no comprehensive explanation has yet emerged. One problem is that acceptance of the fetal allograft is so much the norm that it is difficult to study the mechanism that prevents rejection; if the mechanism for rejecting the fetus is rarely activated, how can one analyze the mechanisms that control it?
The mechanisms contributing to ‘fetomaternal tolerance’ are likely multifactorial and redundant. Although it has been proposed that the fetus is simply not recognized as foreign, women who have borne children often make antibodies directed against the father’s MHC and red blood cell antigens. However, the placenta, which is a fetus-derived tissue, seems to sequester the fetus from the mother’s T cells. The outer layer of the placenta—the interface between fetal and maternal tissues—is the trophoblast. This does not express MHC class II molecules, and expresses only low levels and a restricted subset of MHC class I molecules, making it resistant to direct alloantigen recognition by maternal T cells. Tissues lacking MHC class I expression are, however, vulnerable to attack by NK cells (see Section 3-25). The trophoblast might be protected from attack by NK cells by the expression of a nonclassical and minimally polymorphic HLA class I molecule, HLA-G, which has been shown to inhibit NK killing.