Regulatory T cells in thymic epithelium-induced tolerance. I. Suppression of mature peripheral non-tolerant T cells.
Athymic mice grafted at birth with allogeneic thymic epithelium (TE) display life-long tolerance to tissue grafts of the TE donor strain, in spite of harboring peripheral T cells capable of rejecting those grafts. Tolerance is maintained in these chimeras by TE-specific regulatory CD4 T cells. We presently address the quantification and the mechanisms of this dominant tolerance process. C57BL/6 mice containing variable but defined numbers of peripheral, resident T cells received cell transfers of graded numbers of peripheral T cells from B6(BALB E10) chimeras (C57BL/6 nude mice grafted with TE from 10-day-old BALB/c embryos), resulting in a series of animals containing a wide range of donor (tolerant) versus host (non-tolerant) T cell chimerism. Increasing the relative representation of donor T cells results in a progressive delay in the rejection of BALB/c skin grafts, life-long tolerance being achieved at a ratio of tolerant and non-tolerant T cell populations of 1. In recipients displaying full tolerance, graft-reactive non-tolerant T cells were not deleted, anergized or committed to noninflammatory functions. Thus, sorted host T cells from tolerant recipients readily rejected BALB/c skin grafts upon transfer to immunodeficient animals. Finally, measurements of "helper" and inflammatory activities, as well as interleukin-4 and interferon-gamma production, failed to discriminate between T cell populations from tolerant and non-tolerant animals after specific in vitro stimulation. We conclude that: (a) TE-selected regulatory T cells can suppress, in a quantitative manner, in vivo T cell responses against major and minor histocompatibility antigens expressed by the TE and, (b) this suppressive activity neither inactivates mature non-tolerant T cells, nor does it seem to drive their differentiation along noninflammatory pathways.
Modigliani
Y
Y
Unité d'Immunobiologie, CNRS URA 1961, Institut Pasteur, Paris, France.
Pereira
P
P
Thomas-Vaslin
V
V
Salaün
J
J
Burlen-Defranoux
O
O
Coutinho
A
A
Le Douarin
N
N
Bandeira
A
A
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology; D005260:Female; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000276:immunology*; D017354:Point Mutation; D014407:Tumor Cells, Cultured
D000939:Epitopes; D015689:Oncogene Protein p21(ras)