Human CD8+ T-regulatory cells with low-avidity T-cell receptor specific for minor histocompatibility antigens

Maternal/fetal microchimerism resulting from cell exchanges during pregnancy constitutes a reservoir of persisting alloantigen in mother and adult offspring. These alloantigens induce minor histocompatibility antigen-specific immune responses in both the mother and her offspring, including CD8(+) T regulatory (T(R)) cells with low T-cell receptor binding to major histocompatibility complex tetramers. Although they bind cognate major histocompatibility complex/peptide relatively poorly, these CD8 T(R) nonetheless inhibit high-avidity, tetramer-bright CD8 T effector responding to the same minor H antigen through induction of immunosuppressive DC products. In this review article we explore the mechanisms of such "low-avidity" CD8 T(R)-dependent suppression and discuss their role in naturally acquired tolerance to familial minor histocompatibility antigens encountered during gestation and in parous women. We discuss the implications of our findings for chronic/persisting viral infections, residual tumor burden after cancer treatment and immunotherapy, and renal allograft tolerance.