Partial TCR signals delivered by FcR-nonbinding anti-CD3 monoclonal antibodies differentially regulate individual Th subsets.
Anti-CD3 mAbs with low FcR affinity prolong graft survival in the absence of the cytokine-mediated toxicity observed with conventional anti-CD3 treatment. Previous studies have shown that FcR-nonbinding anti-CD3 mAbs suppress immune responses, at least in part, by delivering a partial signal resulting in Th1 unresponsiveness. In this study, the biochemical and functional consequences of FcR-nonbinding anti-CD3 treatment for various activated T cell populations were examined. In contrast to Th1 cells, FcR-nonbinding anti-CD3-treated Th2 cells secreted IL-4 and proliferated. Furthermore, Th2 cells cultured with the mAb were not rendered unresponsive. Mixed "Th0" populations responded to FcR-nonbinding anti-CD3 by producing IL-4, and showed a selective decrease in IL-2 production following preculture with the mAb. The stimulation of IL-4-producing cells did not reflect a more complete TCR signal, since similar defects in zeta, ZAP-70, and MAP kinase phosphorylation were observed in Th1 and Th2 cells. Despite the proximal signaling defects, FcR-nonbinding anti-CD3 induced nuclear translocation of NF-ATc. Thus, Abs that deliver partial TCR signals may promote development of a Th2 phenotype during the course of an immune response via selective effects on different Th subsets.
Smith
J A
JA
Ben May Institute for Cancer Research, Committee on Immunology, Department of Pathology, University of Chicago, IL 60637, USA.
Tang
Q
Q
Bluestone
J A
JA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D011961:Receptors, Fc / Q000378:metabolism*; D018417:Th1 Cells / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007074:Immunoglobulin G; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011961:Receptors, Fc; D015847:Interleukin-4