The biologic significance of alloreactivity. The ontogeny of T-cell sets specific for alloantigens or modified self antigens

Abstract

We have analyzed the cellular basis of T-cell reactivity against lymphocytes expressing major histocompatibility complex (MHC) products that are foreign by virtue of polymorphism (alloantigens) or because of modification by chemicals or viruses. We find that early in ontogeny, prekiller activity against both trinitrophenyl (TNP)-coupled autologous MHC products and allogeneic MHC products resides in the same (Ly123(+)) T-cell pool; later in ontogeny alloreactivity is invested in Ly23 cells which, when activated, lyse TNP-coupled autologous cells as well as appropriate allogeneic target cells. We demonstrate that stimulation of Ly123(+) T cells in vitro by autologous cells coated with chemically-inactivated Sendai virus results in the formation of Ly23(+) cytolytic T lymphocytes (CTL) that specifically lyse both virus modified autologous target cells and unmodified allogeneic target cells. These results suggest the following model to account for the presence of large numbers of alloreactive T-cell clones in adult animals: continuous stimulation of Ly123 cells by autologous MHC antigens associated with foreign materials such as a virus results in the formation of Ly23 memory progeny carrying receptors that recognize MHC products that are foreign due to genetic polymorphism (alloantigens). In general, these studies indicate that alloaggression (as manifest by Ly23 cells in the CTL response) reflects a high degree of cross stimulation between physiologically relevant antigens, e.g., viral determinants associated with self MHC products, and biologically irrelevant allelic variants of the MHC.