Naive T Cells Are Resistant to Anergy Induction by Anti-CD3 Antibodies

Abstract

Anti-CD3 mAbs are potent immunosuppressive agents used in clinical transplantation. It has been generally assumed that one of the anti-CD3 mAb-mediated tolerance mechanisms is through the induction of naive T cell unresponsiveness, often referred to as anergy. We demonstrate in this study that naive T cells stimulated by anti-CD3 mAbs both in vivo and in vitro do not respond to the superantigen staphylococcal enterotoxin B nor to soluble forms of anti-CD3 mAbs and APC, but express increased reactivity to plastic-coated forms of the same anti-CD3 mAbs and to their nominal Ag/class II MHC, a finding that is difficult to rationalize with the concept of anergy. Phenotypic and detailed kinetic studies further suggest that a strong signal 1 delivered by anti-CD3 mAbs in the absence of costimulatory molecules does not lead to anergy, but rather induces naive T cells to change their mitogen responsiveness and acquire features of memory T cells. In marked contrast, Ag-experienced T cells are sensitive to anergy induction under the same experimental settings. Collectively, these studies demonstrate that exposure of naive T cells in vivo and in vitro to a strong TCR stimulus does not induce Ag unresponsiveness, indicating that sensitivity to negative signaling through TCR/CD3 triggering is developmentally regulated in CD4+ T cells.

Conditional Deletion of PTEN in Peripheral T Cells Augments TCR-Mediated Activation but Does Not Abrogate CD28 Dependency or Prevent Anergy Induction

“…This was examined in Th1 clones, which represents the classical cellular model of T cell anergy (27–29). Anergy was induced using immobilized anti-CD3 mAb, as we and others have reported previously (12, 30).…”

Steady‐state antigen‐expressing dendritic cells terminate CD4+ memory T‐cell responses

“…Conflicting reports indicate that under some circumstances memory CD4 1 T cells are resistant to tolerance induction [20,21], whereas under others, effector CD4 1 T cells appear susceptible [22,23]. In contrast to this, in vitro observations indicate that memory or post-activated CD4 1 T cells are more sensitive than naïve CD4 1 T cells to anergy induction in vitro by fixed APC or agents such as ionomycin and anti-CD3 mAb [24][25][26]. We now demonstrate that CD4 1 effector/memory T-cell responses can be also terminated by cognate antigen-expressing DC.…”

“…Alternatively, the different findings could implicate induction of different molecular pathways for induction of peripheral tolerance in CD4 1 T cells by different APC types. For instance, induction of anergy, or adaptive tolerance, requires induction of many calcium-induced regulatory proteins and pathways such as E3 ubiquitin ligases [34,35] which may be readily induced following Ca 11 mobilization in vitro (or in vivo) by the agents listed above [24][25][26] or by transient antigen presentation in vivo. In contrast, deletion, which requires induction of apoptotic pathways [36], may occur only with the sustained antigen signalling that occurs when antigen is transgenically expressed.…”

Peripheral blood T lymphocyte subsets in children with congenital asplenia

“…Both lymphoproliferation and IFN-gamma production in response to recall antigens remain unchanged in the PBMC of splenectomized patients [14]. ''Memory'' cells also respond well to stimulation with anti-CD3 antibodies [34]. With regard to this, normal responses to anti-CD3 stimulation of PBMC from the CA patients (proliferation, IFN-gamma, TNF-alfa, and IL-6 production) may suggest that the functional status of memory cells remains normal in the CA patients, at least concerning certain parameters studied here.…”