Peripheral autoantigen induces regulatory T cells that prevent autoimmunity - PubMed (original) (raw)
Comparative Study
Peripheral autoantigen induces regulatory T cells that prevent autoimmunity
B Seddon et al. J Exp Med. 1999.
Abstract
Previous studies have shown that autoimmune thyroiditis can be induced in normal laboratory rats after thymectomy and split dose gamma-irradiation. Development of disease can be prevented by reconstitution of PVG rats shortly after their final irradiation with either peripheral CD4(+)CD45RC- T cells or CD4(+)CD8(-) thymocytes from syngeneic donors. Although the activity of both populations is known to depend on the activities of endogenously produced interleukin 4 and transforming growth factor beta, implying a common mechanism, the issue of antigen specificity of the cells involved has not yet been addressed. In this study, we show that the regulatory T cells that prevent autoimmune thyroiditis are generated in vivo only when the relevant autoantigen is also present. Peripheral CD4(+) T cells, from rats whose thyroids were ablated in utero by treatment with 131I, were unable to prevent disease development upon adoptive transfer into thymectomized and irradiated recipients. This regulatory deficit is specific for thyroid autoimmunity, since CD4(+) T cells from 131I-treated PVG.RT1(u) rats were as effective as those from normal donors at preventing diabetes in thymectomized and irradiated PVG.RT1(u) rats. Significantly, in contrast to the peripheral CD4(+) T cells, CD4(+)CD8(-) thymocytes from 131I-treated PVG donors were still able to prevent thyroiditis upon adoptive transfer. Taken together, these data indicate that it is the peripheral autoantigen itself that stimulates the generation of the appropriate regulatory cells from thymic emigrant precursors.
Figures
Figure 1
Morphology of thyroid glands in 131I-treated rats and TxX rats with thyroiditis. Pregnant PVG rats were injected intraperitoneally with 2 mCi of 131I on day 18 of gestation. Thyroid cartilage and attached tissue was removed from normal PVG rats (A) and 131I-treated rats (B) at 8 wk of age, sectioned and stained with hematoxylin and eosin. In the same series of experiments as those described in Fig. 2, whole thyroid glands attached to thyroid cartilage were taken at the time of peak disease from control TxX PVG rats (C), recipients of 107 CD4+ T cells from normal PVG rats (D), and recipients of either 5 × 106 CD4+CD8− thymocytes (E) or 107 CD4+ T cells (F) from the same athyroid donors. Thyroids were frozen, sectioned, and stained with hematoxylin and eosin and are shown at low magnification. (Original magnification: ×50.)
Figure 2
Adoptive transfer of peripheral CD4+ T cells from athyroid donors into TxX rats prevents development of diabetes but not thyroiditis. Athyroid donor PVG and PVG.RT1u rats were generated after exposure to 131I in utero as described in Fig. 1. Normal PVG and PVG.RT1u rats were thymectomized at 3 and 6 wk of age, respectively, and given 1,100 and 1,000 rads of split dose γ-irradiation, respectively, in four equal doses at 2-wk intervals. Shortly after the last irradiation, groups of TxX PVG rats were reconstituted with 5 × 106 CD4+CD8− thymocytes purified from the thymus of either normal or athyroid 8-wk-old PVG donor rats. Further groups of TxX PVG rats were reconstituted with 107 CD4+ T cells purified from the same normal and athyroid PVG donors. Development of anti-Tg IgG responses was monitored for between 4 and 12 wk after the last irradiation by specific ELISA. Data represent peak anti-Tg IgG titers of individual TxX rats, expressed as percentage of standard (A). TxX PVG.RT1u rats were reconstituted shortly after their final irradiation with 107 CD4+ T cells purified from either normal or athyroid 8-wk-old PVG.RT1u rats. The disease incidence of thyroiditis in groups of TxX PVG rats (B) and diabetes in groups of TxX PVG.RT1u rats (C) reconstituted with different cell subsets from different donors are expressed as a percentage of the group. Numbers in parentheses show the actual incidence and group sizes. P values were calculated using Fisher's exact test.
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