Adoptive transfer of autoimmune diabetes and thyroiditis to athymic rats.

Abstract

We describe the induction of autoimmune diabetes, insulitis, and thyroiditis in athymic rats following ujections of major histocompatibiity complex compatible spleen cells. Lymphocytes with these capabilities were found in normal rats ofthe YOS, WAG, PVG, and diabetes-resistant BB strains, and in diabetes-prone BB rats. Adoptive transfer was facilitated by prior in vivo depletion of RT6.1+ regulatory T cells and in vitro mitogen activation of donor spleen cells. By RT6 depleting diabetes-resistant donors and nsing nude recipients, transfer of diabetes and thyroiditis was accomplished by using fresh, unstimulated spleen cells. The data suggest that organ-specific autoreactive cells may be present to various degrees but suppressed to a variable extent in many rat strains. The equilibrium between autoreactive and regulatory cells appears to determine the expression of autoimmunity.Clonal deletion of autoreactive lymphocytes during repertoire development and active suppression of autoreactive cells in peripheral tissues contribute to the prevention of autoimmune diseases (1). In mice, T-lymphocyte populations are deleted in the thymus following interaction with a major histocompatibility complex (MHC) class II (I-E) molecule (2). Nonobese diabetic mice do not express I-E and develop autoimmune diabetes (3). These mice harbor T-cell populations normally deleted in I-E-expressing strains (4). In B6AF1 mice, neonatal thymectomy induces organ-specific autoimmunity (5). Thymectomy earlier or later is ineffective, suggesting that a sequence ofintrathymic events culminates in an immunological definition of self.Evidence for suppression of autoreactive T cells in peripheral tissues is also accumulating. Transplantation of Lyt-1-depleted spleen cells from nu/+ mice (6) or thymuses from cyclosporin-treated nu/+ mice (7) into nu/nu recipients results in autoimmune endocrinopathy. This can be prevented by cotransplantation of a nu/+ thymus or unfrictionated spleen cells together with the cyclosporin-treated thymus.An imbalance between autoreactive and regulatory (RT6+) cells may in part determine the expression of BB rat autoimmunity (8). Diabetes-prone (DP) BB rats are lymphopenic and deficient in T cells that express the RT6 alloantigen (9). They spontaneously develop insulitis, hyperglycemia, and thyroiditis (8,10 ITo whom reprint requests should be addressed. 7618The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.Proc. Natl. Acad. Sci. USA 87 (1990) 7619 isolated splenocytes were injected into recipients (108 cells in 0.5 ml per rat).Flow Microfluorimetry. To determine the number of native T cells present in athymic rats and to assay for chimerism in adoptive recipients, lymph node cell suspensions were labeled with 0X19 mouse anti-rat CD5 (pan-T cell) monoclonal antibody (mAb), with the rat anti-RT6.1 mAb DS4.23, or with the rat anti-RT6.2 mAb 6A5 (9). Cell...

Prevention of spontaneous immune-mediated diabetes development in the LEW.1AR1-iddm rat by selective CD8+ T cell transfer is associated with a cytokine shift in the pancreas-draining lymph nodes

“…Thus, a clear autoaggressive potential of CD4 + T cells was seen, in line with several studies on BB-DP rats and NOD mice [7][8][9][10][11][12]. The predominant role of CD4 + T cells has been previously demonstrated by selective transfer of CD4 + or CD8 + T cells in immunodeficient NOD strains, whereas CD8 + T cell subsets were not diabetogenic [7,16].…”

“…The only difference between the LEW.1AR1-iddm rat and the background strain is a mutation on chromosome 1 within Iddm8 (RNO1q43-51) [4,5]. Adoptive transfer of T cells from diabetic LEW.1AR1-iddm rats to prediabetic LEW.1AR1-iddm rats significantly increased the incidence of diabetes [6] in agreement with studies on NOD mice and BB-DP rats [7][8][9][10][11][12]. The autoreactive potential can be transferred through immune cells from diabetic LEW.1AR1-iddm rats into athymic nude LEW.1AR1-Whn rnu animals, but not to the diabetes-resistant LEW.1AR1 background strain [6].…”

Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter

“…Thirty years ago, it was proposed that subsets of thymus-derived CD4 T cells are essential to actively suppress immune responses and maintain self-tolerance (1)(2)(3). Recent studies have identified specific regulatory T cells that likely explain these phenomena (4)(5)(6)(7). Subsets of regulatory T cells have been described, and they share common features of being hypoproliferative to T cell antigen receptor (TCR) stimulation in vitro and immunosuppressive in vitro and in vivo.…”

Regulatory T cells – a brief history and perspective

“…Attempts were made to separate the two putative CD4 + populations in normal naive mice by the expression of cell surface molecules [20][21][22][23][24][25][26] (Fig. 1C).…”