Acquisition of regulatory function by human CD8⁺ T cells treated with anti‐CD3 antibody requires TNF

Abstract

Anti-CD3 mAb can modulate graft rejection and attenuate autoimmune diseases but their mechanism(s) of action remain unclear. CD8 1 T cells with regulatory function are induced in vitro by Teplizumab, a humanized anti-CD3 antibody and inhibit responses of autologous and allogeneic T cells. They inhibit CD4 1 T-cell proliferation by mechanisms involving TNF and CCL4, and by blocking target cell entry into G2/M phase of cell cycle but neither kill them, nor compete for IL-2. CD8 1 Treg can be isolated from peripheral blood following treatment of patients with Type 1 diabetes with Teplizumab, but not from untreated patients. The induction of CD8 1 Treg by anti-CD3 mAb requires TNF and signaling through the NF-jB cascade. The CD8 1 Treg express CD25, glucocorticoid-induced TNF receptor family, CTLA-4, Foxp3, and TNFR2, and the combined expression of TNFR2 and CD25 identifies a potent subpopulation of CD8 1 Treg. These studies have identified a novel mechanism of immune regulation by anti-CD3 mAb and markers that may be used to track inducible CD8 1 Treg in settings such as chronic inflammation or immune therapy.

Anti-CD3 clinical trials in type 1 diabetes mellitus

“…In T1D patients treated with otelixizumab, a rise in CD8+ T cells was also observed but many of the cells were identified by Class I MHC tetramer staining as Epstein-Barr virus (EBV) reactive, suggesting that the increase in CD8+ cells in those subjects was a consequence of EBV reactivation and many were viral antigen specific [33]. Nonetheless, CD8 + T cells isolated directly from teplizumab but not placebotreated patients showed inhibitory properties in a Treg assay, suggesting that the expanded CD8+ cells had regulatory function [34].…”

EBV infection and anti-CD3 treatment for Type 1 diabetes: bad cop, good cop?

“…It has been known for decades that EBV, as part of the innate host response, is a potent inducer of host TNF. Some of the regulatory immune function of anti-CD3 requires TNF [4]. TNF has been known in animal models to suppress or prevent onset of T1D by selectively destroying insulin-autoreactive T cells and inducing beneficial Treg cells, according to diverse evidence [5–7].…”

Characterization of antigen-binding and MHC class II-bearing T cells with suppressive activity in response to tolerogenic stimulus

“…Although CD8-positive cells are generally considered to represent cytotoxic T cells, Liu et al (1998) have described CD8 + CD28 + regulatory T cells to suppress T cell alloreactivity, while Zhang et al (2000) described CD8-class I restricted T cells able to suppress CD8 + CD28 + CTLs and skin allograft rejection. In addition, Ablamunits et al (2010) have described CD8 + T cells with regulatory function to be induced in vitro by a humanized anti-CD3 antibody and inhibit responses of autologous and allogeneic T cells, while expressing CD25, CTLA-4, Foxp3, and TNFR2. Furthermore, CD152 is known to replace CD28 in order to shut down an ongoing immune response, acting thus as a suppressive signal (Pentcheva-Hoang et al 2000;Perez et al 1997).…”