Inhibition of murine nephritogenic effector T cells by a clone-specific suppressor factor.
We have used a murine model of organ-specific autoimmunity to characterize therapeutic modalities capable of down-regulating the cellular limb of the autoimmune response. Murine interstitial nephritis is an autoimmune disease mediated by tubular antigen-specific CD8+ nephritogenic effector T cells which are delayed-type hypersensitivity (DTH) reactive and cytotoxic to renal epithelial cells. Previous studies have demonstrated that disease can be suppressed with experimentally induced populations of T cells (Ts1 and Ts2 cells) obtained after injection of tubular antigen-coupled splenocytes into syngeneic mice. As the target of Ts2 is the CD8+ effector T cell, we have evaluated its effects on nephritogenic effector T cell clones isolated from diseased animals. Our studies demonstrate that soluble proteins expressed by Ts2 cells (TsF2) specifically abrogate the DTH, cytotoxic, and nephritogenic potential of M52 cells, although T cell receptor and IL-2 receptor expression are unchanged in these unresponsive M52 clones. TsF2-induced inhibition is dependent on new mRNA and protein synthesis. In a cytotoxic clone, M52.26, exposure to TsF2 induces expression of TGF-beta 1 which is, in turn, required for inhibition of cytotoxicity and nephritogenicity. Our studies are consistent with TGF-beta 1 behaving, at least in some T cells, as a nonspecific final effector of clone-specific suppression.
Renal-Electrolyte Division, University of Pennsylvania School of Medicine, Philadelphia 19104.
C M
CM
Meyers
C J
CJ
Kelly
D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology*; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D016207:Cytokines / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D006968:Hypersensitivity, Delayed; D007106:Immune Sera / Q000276:immunology; D016219:Immunotherapy, Adoptive; D051379:Mice; D008969:Molecular Sequence Data; D009395:Nephritis, Interstitial / Q000209:etiology*; D011817:Rabbits; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D013491:Suppressor Factors, Immunologic / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology
D016207:Cytokines; D007106:Immune Sera; D011948:Receptors, Antigen, T-Cell; D013491:Suppressor Factors, Immunologic; D016212:Transforming Growth Factor beta