title: B220+ double-negative T cells suppress polyclonal T cell activation by a Fas-independent mechanism that involves inhibition of IL-2 production.
abstract: Fas-mediated apoptosis is a key mechanism for elimination of autoreactive T cells, yet loss of function mutations in the Fas signaling pathway does not result in overt T cell-mediated autoimmunity. Furthermore, mice and humans with homozygous Fas(lpr) or Fas ligand(gld) mutations develop significant numbers of B220+ CD4- CD8- double-negative (DN) alphabeta T cells (hereafter referred to as B220+ DN T cells) of poorly understood function. In this study, we show that B220+ DN T cells, whether generated in vitro or isolated from mutant mice, can suppress the ability of activated T cells to proliferate or produce IL-2, IL-10, and IFN-gamma. B220+ DN T cells that were isolated from either lpr or gld mice were able to suppress proliferation of autologous and syngeneic CD4 T cells, showing that suppression is Fas independent. Furthermore, restoration of Fas/Fas ligand interaction did not enhance suppression. The mechanism of suppression involves inhibition of IL-2 production and its high affinity IL-2R alpha-chain (CD25). Suppression also requires cell/cell contact and TCR activation of B220+ DN T cells, but not soluble cytokines. These findings suggest that B220+ DN T cells may be involved in controlling autoreactive T cells in the absence of Fas-mediated peripheral tolerance.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland/Ross 659, Baltimore, MD 21205, USA. ahamad@jhmi.edu
authors.forename: Abdel Rahim A
authors.initials: AR
authors.lastname: Hamad
authors.forename: Abdiaziz S
authors.initials: AS
authors.lastname: Mohamood
authors.forename: Crystal J
authors.initials: CJ
authors.lastname: Trujillo
authors.forename: Ching-Tai
authors.initials: CT
authors.lastname: Huang
authors.forename: Emily
authors.initials: E
authors.lastname: Yuan
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Schneck
mesh_terms: D000818:Animals; D002999:Clone Cells; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D019014:fas Receptor; D017493:Leukocyte Common Antigens