Development of CD4⁻CD8⁺ cytotoxic T cells requires interactions with class I MHC determinants

Abstract

Differentiation of bone marrow derived precursors into mature T cells takes place in the thymus. During differentiation, T cells develop the receptor repertoire which allows them to recognize antigen in the context of self major histocompatibility complex (MHC) molecules. Mature T helper cells (mostly CD4⁺CD8⁻) recognize antigen in the context of class II MHC molecules, whereas cytotoxic T cells (mostly CD4⁻CD8⁺) recognize antigen in the context of class I MHC determinants^1,2. Thymic MHC-encoded determinants greatly influence the selection of the T-cell receptor repertoire^3–6. In addition to positive selection, a negative selection to eliminate self-reactive T-cell clones is thought to occur in the thymus⁷, but how this 'education' occurs is not well understood. It has been suggested that during differentiation an interaction between the T-cell receptor (TCR) and MHC-encoded determinants occurs, leading to the selection of an MHC-restricted receptor repertoire^3–5. In support of this hypothesis, class-II-specific, CD4⁺CD8⁻ helper T cells fail to develop in mice neo-natally treated with anti-class II monoclonal antibody (mAb)^8,9. As CD4⁻CD8⁺ cells differ from the CD4⁺CD8⁻ lineage (in function, MHC-restriction specificity and perhaps site of education^1,2,10) we examined whether interactions with MHC determinants are also necessary for the development of class-I-specific T cells. Here we show that mice chronically treated with anti-class I mAb from birth lack CD4⁻CD8⁺ cells and cytotoxic T-cell precursors, indicating that most CD4⁻CD8⁺ T cells need interaction with class I MHC molecules during differentiation.