Long-term persistence of CD4+ but rapid disappearance of CD8+ T cells expressing an MHC class I-restricted TCR of nanomolar affinity

Abstract

Most T cells have T cell receptors (TCR) of micromolar affinity for peptide-major histocompatibility complex (MHC) ligands, but genetic engineering can generate TCRs of nanomolar affinity. The affinity of the TCR used, m33, for its cognate non-self peptide-MHC-I complex (SIYRYYGL-K b) is 1,000-fold higher than of the wild-type TCR 2C. The affinity of m33 for the self-peptide dEV-8 on K b is only twofold higher. Mouse CD8+ T cells transduced with an m33-encoding retrovirus showed binding of SIY-K b and potent function in vitro, but in vivo these T cells disappeared within hours after transfer into syngeneic hosts without causing graft-versus-host disease (GVHD). Accordingly, in cases where such CD8-dependent self-reactivity might occur in human adoptive T cell therapies, our results show that a peripheral T-cell deletion mechanism could operate to avoid reactions with the host. In contrast to CD8+ T cells, we show that CD4+ T cells expressing m33 survived for months in vivo. Furthermore, the m33-transduced CD4+ T cells were able to mediate antigen-specific rejection of 6-day-old tumors. Together, we show that CD8+ T cell expressing a MHC class I-restricted high-affinity TCR were rapidly deleted whereas CD4+ T cells expressing the same TCR survived and provided function while being directed against a class I-restricted antigen. © The American Society of Gene & Cell Therapy.