In vivo administration of anti-murine CD3 monoclonal antibody induces selective, long-term anergy in CD8+ T cells.
The purpose of this study was to determine the short-term and long-term effects of repeated daily administration of low dose anti-CD3 monoclonal antibody (mAb) on CD4+ and CD8+ T cell number and function. Daily (7 days) administration of low doses (5 microg) of mitogenic (whole) or nonmitogenic (F(ab')2, fragments) anti-CD3 mAb resulted in depletion of CD4+ and CD8+ T cells in both lymph node and spleen that, in the case of whole mAb, persisted for several months in thymectomized animals. CD3+ cells obtained from thymectomized animals treated with whole but not F(ab')2 fragments of anti-CD3 mAb demonstrated decreased proliferation to anti-CD3 mAb in vitro (on a per cell basis as compared with control animals). Although purified CD4+ cells from animals treated with whole mAb demonstrated only slightly decreased proliferative responses to anti-CD3 mAb in vitro, purified CD8+ cells demonstrated an almost complete loss of their proliferative response. Studies in thymectomized animals demonstrated that the profound CD8+ cell hyporesponsiveness persisted for at least 5 months after anti-CD3 treatment. These effects were not observed in nonthymectomized animals, however, suggesting that recovery of CD8+ T cell function is caused by repopulation of lymphoid organs by thymic-derived CD8+ T cells. Additional studies with purified CD8+ cells from anti-CD3 mAb-treated animals indicated that the hyporesponsiveness was not caused by alterations in T cell receptor (TCR) expression. However, proliferative responses of anergic CD8+ T cells to phorbol ester and ionomycin were comparable to those of control CD8+ T cells. After in vitro stimulation, CD8+ cells from anti-CD3 treated animals did not produce interleukin (IL)-2, and although they retained their ability to upregulate IL-2 receptor expression (albeit reduced by about 50% compared with CD8+ cells from control animals), proliferative responses were not restored by addition of exogenous IL-2. In addition to IL-2 receptor expression, CD8+ cells from anti-CD3-treated animals also demonstrated an ability to upregulate CD44 and LFA-1 expression upon reexposure to anti-CD3 mAb in vitro. In conclusion, treatment with daily administration of low doses of whole or F(ab')2 fragments of anti-murine CD3 mAb induces significant T cell depletion in secondary lymphoid organs and does not seem to alter CD4+ proliferative responses in vitro, but whole mAb (and not F(ab')2 fragments) profoundly suppresses CD8+ proliferative responses. The profound hyporesponsiveness of CD8+ T cells induced by whole anti-murine CD3 mAb (1)persists for at least persists for at least several months, (2) is characterized by decreased IL-2 production and responsiveness to IL-2, and (3) recovery of CD8+ cell function is likely mediated by repopulation of lymphoid organs by thymic-derived CD8+ cells.
Woodle
E S
ES
Department of Surgery, University of Chicago, Illinois 60637, USA.
Hussein
S
S
Bluestone
J A
JA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006224:Cricetinae; D018960:Hyaluronan Receptors / Q000032:analysis; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000096:biosynthesis; D008212:Lymphocyte Depletion; D016169:Lymphocyte Function-Associated Antigen-1 / Q000032:analysis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013934:Thymectomy
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D018960:Hyaluronan Receptors; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D015375:Receptors, Interleukin-2