CD4+CD25+ T cells in mice and rats are capable of transferring protection against organ‐specific autoimmune disease and colitis and suppressing the proliferation of other T cells after polyclonal stimulation in vitro. Here we describe the existence in humans of CD4+CD25+ T cells with the same in vitro characteristics. CD4+CD8–CD25+ T cells are present in both the thymus and peripheral blood of humans (∼ 10 % of CD4+CD8– T cells), proliferate poorly in response to mitogenic stimulation and suppress the proliferation of CD4+CD25– cells in co‐culture. This suppression requires cell contact and can be overcome by the addition of exogenous IL‐2. CD4+CD25+ cells from thymus and blood were poor producers of IL‐2 and IFN‐γ, and suppressed the levels of these cytokines produced by CD4+CD25– cells. However, CD4+CD25+ PBL produced higher levels of IL‐4 and similar amounts of IL‐10 as CD4+CD25– cells. Regulatory CD4+CD25+ T cells have an activated phenotype in the thymus with expression of CTLA‐4 and CD122 (IL‐2Rβ). The fact that CD4+CD25+ regulatory T cells are present with a similar frequency in the thymus of humans, ratsand mice, suggests that the role of these cells in the maintenance of immunological tolerance is an evolutionarily conserved mechanism.
SummaryDiabetes was induced in a normal nonautoimmune rat strain by rendering the animals relatively T cell deficient using a protocol of adult thymectomy and sublethal 3' irradiation. All male rats and 70% of females developed an acute syndrome with severe loss of weight and hyperglycemia. Diabetes in these lymphopoenic rats was associated with extensive insulitis involving CD4 + and CD8 + T cells and macrophages. The CD8 + T cells were essential for the development of diabetes but not insulitis. The autoimmune diabetes and insulitis were completely prevented by the injection of a particular CD4 + T call subset, isolated from healthy syngeneic donors, of the phenotype CD45RC l~ T cell receptor cx/fl + KT6 § Thy-1-OX-40-. Cells of this protective phenotype, which make up about 5% of thoracic duct lymphocytes, were found to provide help for secondary antibody responses and produce interleukin 2 (II-2) and I1-4, but no interferon % on in vitro activation. These data provide evidence for the presence of autoreactive T cells in the normal immune system of the rat and reveal that in the intact animal these cells are prevented from expressing their autoreactive potential by other T cells.
SummaryCongenitally athymic rats injected with CD45RBhigh CD4+ T cells from congenic euthymic donors developed a severe wasting disease with inflammatory infiltrates in liver, lung, stomach, thyroid, and pancreas . In contrast, recipients of CD45RB1°w CD4+ T cells remained well and continued to gain weight . Animals given unfractionated CD4+ T cells, i.e., a mixture of approximately two-thirds CD45RBhieh and one-third CD45RB 1°"', were protected from the wasting disease, and the incidence of organ-specific inflammation was much reduced compared with that found in recipients of CD45RBh'gh cells alone. The data suggest that this latter subset of CD4+ T cells has autoaggressive potential that is inhibited in normal animals by cells of the CD45RB10 W CD4+ phenotype. The possible consequences of a breakdown in this immunoregulatory mechanism are briefly discussed.
Previously we have shown that autoimmune diabetes, induced in rats by a protocol of adult thymectomy and split-dose gamma irradiation, can be prevented by the transfer of a subset of CD4+ T cells with a memory phenotype (CD45RC−), as well as by CD4+CD8− thymocytes, from syngeneic donors. Further studies now reveal that in the thymus the regulatory cells are observed in the CD25+ subset of CD4+CD8− cells, whereas transfer of the corresponding CD25− thymocyte subset leads to acceleration of disease onset in prediabetic recipients. However, in the periphery, not all regulatory T cells were found to be CD25+. In thoracic duct lymph, cells that could prevent diabetes were found in both CD25− and CD25+ subsets of CD4+CD45RC− cells. Further, CD25− regulatory T cells were also present within the CD4+CD45RC− cell subset from spleen and lymph nodes, but were effective in preventing diabetes only after the removal of CD25− recent thymic emigrants. Phenotypic analysis of human thymocytes showed the presence of CD25+ cells in the same proportions as in rat thymus. The possible developmental relationship between CD25+ and CD25− regulatory T cells is discussed.
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