CD4⁺CD25⁺ regulatory cells in acquired MHC tolerance

Abstract

Tolerance to self-antigens is an ongoing process that begins centrally during T-cell maturation in the thymus and continues throughout the cell's life in the periphery by a network of regulated restraints. Remaining self-reactive T-cells that escape intrathymic deletion may be silenced within the peripheral immune system by specialized regulatory CD4+ cells. By analogy, regulatory CD4+ cells that control immunity to "acquired self" should arise in circumstances where the immune system acquires tolerance to foreign MHC, such as the tolerance that develops following the exposure to foreign MHC antigens during the neonatal period. We have used this classic model of neonatal tolerance to examine the role of regulatory CD4+ cells in acquired tolerance to disparate class I and class II MHC. Adoptive transfer of unfractionated but not CD4+-depleted spleen cells from neonatal tolerant mice into SCID recipients inhibited skin graft rejection by immunocompetent CD8+ T cells. Using 5-bromo-2'-deoxyuridine incorporation, standard cytotoxic T-lymphocyte assays, short-term interferon-gamma ELISPOT, and intracellular FACS analysis to study CD8+ T-cell effector function, we demonstrated that neonatal tolerant mice contain CD4+CD25+ cells that suppress the development of anti-donor CD8+ T-cell responses in vitro. We conclude that regulatory CD4+CD25+ cells initiate and/or maintain tolerance by preventing the development of CD8+ T-cell alloreactivity.

Murine neonates develop vigorous in vivo cytotoxic and Th1/Th2 responses upon exposure to low doses of NIMA-like alloantigens

“…Experimental transplantation of high doses of allogeneic cells results in tolerance, [13][14][15][16][17][18][19][20][21] and there are reports that this effect may be mediated by regulatory T cells (T regs ). 62 Recent studies using a NIMA mouse model have demonstrated that mice that accepted allogeneic heart grafts exhibit donor microchimerism, 23 and possess higher frequencies of T regs and TGF-␤ ϩ IL-10 ϩ CD4 ϩ cells than mice that rejected their allografts. 23,24 However, tolerance to NIMA-bearing heart allografts was observed only when the mice were exposed to NIMA both in utero and after birth via breast milk.…”

Absence of clinical GVHD and the in vivo induction of regulatory T cells after transplantation of facilitating cells

“…This demonstrates a marked trend toward increased gene expression of the immunosuppressive cytokine TGF-␤ after FC transplantation (P ϭ .2; Student t test.). Given the importance of TGF-␤ in inducing immunoregulatory tolerance, 26,27 the trend toward increased TGF-␤ gene expression in HSCϩFC recipients suggested that the FC is a regulatory T cell or that regulatory T cells are induced after FC transplantation.…”

Identification of a novel natural regulatory CD8 T-cell subset and analysis of its mechanism of regulation

“…1,2,[16][17][18][19] These results demonstrate that the immune system from healthy animals contains natural regulatory CD4 T cells that actively suppress autoreactivity. In animal models, several studies have shown that regulatory CD4 T cells, besides their pivotal role in maintaining self-tolerance, also regulate homeostasis of the peripheral T-cell pool, 20 contribute to tolerance induction after solid organ transplantation, 21,22 and promote tolerance to allogeneic bone marrow grafts. 23,24 These findings have opened new prospects for immunotherapeutic interventions.…”