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International Immunology, Vol. 12, No. 1, 57-66, January 2000
© 2000 Japanese Society for Immunology

Differential susceptibility of human Th1 versus T h 2 cells to induction of anergy and apoptosis by ECDI/antigen-coupled antigen-presenting cells

Arthur A. Vandenbark1,2,3, David Barnes1, Tom Finn1,3, Dennis N. Bourdette1,3, Ruth Whitham1,3, Ian Robey1, Johnan Kaleeba2, Bruce F. Bebo, Jr1,3, Steven D. Miller4, Halina Offner1,3 and Yuan K. Chou1,3

1 Neuroimmunology Research R & D-31, Veterans Affairs Medical Center, Portland, OR 97201, USA
2 Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, OR 97201, USA
3 Department of Neurology, Oregon Health Sciences University, Portland, OR 97201, USA
4 Department of Microbiology–Immunology, Northwestern University Medical School, Chicago, IL, USA

Correspondence to: A. A. Vandenbark, Neuroimmunology Research R & D-31, Veterans Affairs Medical Center, Portland, OR 97201, USA

Antigen-coupled antigen-presenting cells (APC) serve as potent tolerogens for inhibiting immune responses in vivo and in vitro, apparently by providing an antigen-specific signal through the TCR in the absence of co-stimulation. Although this approach has been well studied in rodents, little is known about its effects on human T cells. We evaluated the specificity and mechanisms of tolerization of human T cells in vitro using monocyte-enriched adherent cells that were pulsed with antigen and treated with the cross-linker, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (ECDI). Autologous antigen-coupled APC selectively tolerized T cells of the Th1 but not Th2 lineage through a mechanism that involved both antigen-specific and antigen-non-specific elements. The tolerization process was dependent on the ECDI and antigen concentration, and the coupling time, and was reflected by initial up-regulation of CD25. However, upon re-stimulation with fresh APC and antigen, tolerized Th1 cells failed to proliferate or to produce Th1 cytokine message or secreted protein, had decreased expression of CD25, CD28 and B7 and increased expression of MHC class II molecules, and demonstrated an enhanced commitment to apoptosis. Th1 cell tolerization could be prevented by adding anti-CD28 antibody, IL-2 or untreated APC at the same time as the ECDI/antigen-coupled APC, or reversed by adding anti-CD28 antibody or IL-2 upon re-stimulation with fresh APC plus antigen. Thus, the tolerizing effect of ECDI/antigen-coupled APC on human Th1 cells appears to involve a reversible anergy mechanism leading to apoptosis, whereby the targeted T cells receive full or partial activation through the TCR, without coordinate co-stimulation. These data suggest dichotomous signaling requirements for inactivating cells of the Th1 and Th2 lineages that may have important implications for treatment of Th1-mediated autoimmune or inflammatory diseases.

Keywords: altered antigen-presenting cells, human T cells, tolerance induction

Transmitting editor: L. Steinman


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