Thymectomy of susceptible strains of mice on day 3 of life results in a spectrum of organ-specific autoimmunity that can be prevented by reconstitution of the thymectomized animals early in life with normal adult lymphocytes. The effectors and suppressors of autoimmunity in this model have been convincingly shown to be CD4+ T cells. It has been demonstrated recently that the regulatory CD4+ T cells that prevent disease coexpress CD25. We have further characterized the population of CD4+CD25+ immunoregulatory cells and demonstrated that they can suppress not only the induction of disease post-thymectomy, but can also efficiently suppress disease induced by cloned autoantigen-specific effector cells. Furthermore, the CD4+CD25+ T cells appear to be members of a unique lineage of regulatory T cells, as the induction of CD25 expression on a monospecific population of T cells derived from TCR transgenic SCID mice did not result in suppression of post-thymectomy autoimmunity. In addition, the TCR transgenic SCID mice were highly susceptible to autoimmune disease induced by the cloned line of autoantigen-specific effectors, while normal mice were relatively resistant. The capacity of the cloned line to transfer disease to nu/nu recipients could be inhibited by normal spleen cell populations containing CD4+CD25+ cells and by purified CD4+CD25+ cells. Although the target Ag(s) and mechanism of action of the CD4+CD25+ T cells remain to be determined, it is likely that they also play an important role in modulating other autoimmune diseases that are mediated by activation of "ignorant" self-reactive T cells present in the normal peripheral lymphocyte pool.

CD4+CD25+ T Cells Inhibit Both the Induction and Effector Function of Autoreactive T Cells and Represent a Unique Lineage of Immunoregulatory Cells

In 1973 two groups reported the induction of organ-specific autoimmune diseases by T cell deprivation. Penhale and co-workers (Penhale et al. 1973) found that autoimmune thyroiditis could be induced in 5-week-old Wistar rats by thymeclomy and repeated low-dose irradiation. On the other hand, Nishizuka and colleagues (Nishizuka et al. 1973) made the fascinating observation that autoimmune thyroiditis spontaneously developed in mice following thymectomy alone, so long as the thymectomy was carried out in the neonatal period. Subsequently, neonatal thymectomy was shown to induce a wide variety of organ-specific autoimmune diseases in mice, with different strains showing differences in disease susceptibility. The overlap in autoimmune diseases in this mouse model is reminiscent of the overlap observed in the endocrine organ/stomach cluster of organ-specific autoimmune diseases of humans. From 1975 onwards a number of other manipulations of the immune system have been shown to induce organ-specific autoimmune diseases in rodents. A common characteristic of these manipulations is either a deficit of T cells or reduction of the TCR repertoire, in other words functional T cell lymphopenia. The range of autoimmune diseases induced by these manipulations is most impressive and includes diabetes, thyroditis, gastritis, orchitis, oophoritis, prostatitis, and coagulating adenitis. Many of these diseases are rare in laboratory strains of rats and mice. Evidence that the autoimmune diseases are due to specific immune responses is supported by the presence of infiltrating lymphocytes in the target organ, circulat-

Organ-specific autoimmunity induced by lymphopenia.

Many autoimmune diseases are characterized by autoantibody reactivities to multiple cellular antigens. Autoantigens are commonly defined as targets of the autoimmune B cell response, but the role, if any, of these autoantigens in T cell-mediated autoimmune diseases is generally unknown. Murine experimental autoimmune gastritis is a CD4+ T cell-mediated organ-specific autoimmune disease induced by neonatal thymectomy of BALB/c mice. The murine disease is similar to human autoimmune gastritis and pernicious anemia, and is characterized by parietal and chief cell loss, submucosal mononuclear cell infiltrates, and autoantibodies to the alpha and beta subunits of the gastric H/K ATPase. However, the specificity of T cells that cause the disease is not known. To examine the role of the H/K ATPase in this T cell-mediated disease, transgenic mice were generated that express the beta subunit of the H/K ATPase under the control of the major histocompatibility complex class II I-Ek alpha promoter. We show that transgenic expression of the gastric H/K ATPase beta subunit specifically prevents the onset of autoimmune gastritis after neonatal thymectomy. In addition, thymocyte transfer experiments suggest that tolerance of pathogenic autoreactive T cells is induced within the thymus of the transgenic mice. We conclude that the beta subunit of the gastric H/K ATPase is a major T cell target in autoimmune gastritis and that thymic expression of a single autoantigen can abrogate an autoimmune response to multiple autoantigens.

https://rupress.org/jem/article-pdf/178/2/419/1268162/419.pdf

An autoimmune-disease with multiple molecular targets abrogated by the transgenic expression of a single autoantigen in the thymus

https://www.gastrojournal.org/article/S0016-5085(01)76954-5/pdf

H(+),K(+)-atpase (proton pump) is the target autoantigen of Th1-type cytotoxic T cells in autoimmune gastritis.

Thymic epithelial cells (TEC) form the structural and functional microenvironment necessary for the establishment and quality control of the T cell repertoire. In addition, they provide an ectopic source of numerous tissue-restricted antigens (TRA), a feature called promiscuous gene expression (pGE). How the regulation of pGE is related to the cell biology of TEC subset(s), e.g. their turnover and developmental interrelationship is still poorly understood. The observation that pGE is foremost a property of phenotypically and functionally mature medullary TEC (mTEC) implies that the full implementation of pGE is contingent on mTEC differentiation. Here, we show that the emergence of TEC subsets and pGE is tightly correlated during ontogeny and we provide evidence that mature CD80pos mTEC develop from an immature CD80neg subset. This differentiation step proceeds continuously in the postnatal thymus. While mature mTEC turnover in 2 to 3 weeks, immature mTEC encompass a smaller cycling and a larger non-cycling pool. The latter might serve as a reservoir of committed precursors, which sustain this renewal process. Our data document that mTEC represent a highly dynamic cell population, and they imply that the availability and display of TRA in the thymus undergoes a perpetual temporal and spatial reorganization.

Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells.

https://www.gastrojournal.org/article/0016-5085(91)90002-3/pdf

Yumiko Mori

Papers

The parietal cell autoantibodies recognized in neonatal thymectomy-induced murine gastritis are the α and β subunits of the gastric proton pump