In vivo mechanisms of acquired thymic tolerance.

TY - JOUR

T1 - In vivo mechanisms of acquired thymic tolerance.

AU - Chen, W

AU - Issazadeh-Navikas, Shohreh

AU - Sayegh, M H

AU - Khoury, S J

N1 - Keywords: Adoptive Transfer; Animals; CD4-Positive T-Lymphocytes; Cell Movement; Epitopes; Immune Tolerance; Injections, Intralymphatic; Interferon Type II; Interleukin-2; Kinetics; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Transgenic; Ovalbumin; Receptors, Antigen, T-Cell; Recombinant Proteins; Th1 Cells; Thymectomy; Thymus Gland

PY - 1997

Y1 - 1997

N2 - Injection of antigen into the thymus of adult animals induces specific systemic tolerance, but the mechanisms of acquired thymic tolerance are not well understood. To investigate these mechanisms we used a model of intrathymic injection of ovalbumin (OVA) in BALB/c mice. We show an antigen-specific decrease in proliferative responses to OVA, as well as a significant decrease in antigen-specific IL-2 secretion and IFN-gamma production by splenocytes and lymph node cells of tolerant mice. Addition of recombinant IL-2 in vitro reversed the defect in IFN-gamma production by cells from OVA-tolerized animals, but did not reverse the proliferation or IL-2 production defects. By using an adoptive transfer system, where a small population of OVA peptide-specific CD4+ TCR transgenic T cells are transferred into syngeneic normal recipients, we show an absence of peripheral antigen-dependent clonal expansion of transferred CD4+ TCR transgenic cells in tolerant mice in vivo. There was an increase in clonotype-positive T cells in the thymus after immunization, confirming that activated T cells circulate through the thymus. Furthermore, thymectomy after intrathymic injection abrogates the effect of acquired thymic tolerance and restores antigen-dependent clonal expansion in vivo. We conclude that intrathymic injection of antigen induces Th1 cell unresponsiveness and prevents the peripheral expansion of antigen-specific CD4(+) T cells in vivo. This is the first demonstration that in acquired thymic tolerance antigen-specific T cells circulate to the thymus where they may be anergized or ultimately deleted.

AB - Injection of antigen into the thymus of adult animals induces specific systemic tolerance, but the mechanisms of acquired thymic tolerance are not well understood. To investigate these mechanisms we used a model of intrathymic injection of ovalbumin (OVA) in BALB/c mice. We show an antigen-specific decrease in proliferative responses to OVA, as well as a significant decrease in antigen-specific IL-2 secretion and IFN-gamma production by splenocytes and lymph node cells of tolerant mice. Addition of recombinant IL-2 in vitro reversed the defect in IFN-gamma production by cells from OVA-tolerized animals, but did not reverse the proliferation or IL-2 production defects. By using an adoptive transfer system, where a small population of OVA peptide-specific CD4+ TCR transgenic T cells are transferred into syngeneic normal recipients, we show an absence of peripheral antigen-dependent clonal expansion of transferred CD4+ TCR transgenic cells in tolerant mice in vivo. There was an increase in clonotype-positive T cells in the thymus after immunization, confirming that activated T cells circulate through the thymus. Furthermore, thymectomy after intrathymic injection abrogates the effect of acquired thymic tolerance and restores antigen-dependent clonal expansion in vivo. We conclude that intrathymic injection of antigen induces Th1 cell unresponsiveness and prevents the peripheral expansion of antigen-specific CD4(+) T cells in vivo. This is the first demonstration that in acquired thymic tolerance antigen-specific T cells circulate to the thymus where they may be anergized or ultimately deleted.

U2 - 10.1006/cimm.1997.1165

DO - 10.1006/cimm.1997.1165

M3 - Journal article

C2 - 9268500

SN - 0008-8749

VL - 179

SP - 165

EP - 173

JO - Cellular Immunology

JF - Cellular Immunology

IS - 2

ER -