Thymic selection process induced by hybrid antibodies

Abstract

Thymus-derived (T) lymphocytes using the αβ T-cell antigen receptor (TCR) recognize fragmented antigen in conjunction with surface molecules encoded by genes of the major histocompatibility complex (MHC)^1–6. Peripheral T lymphocytes preferentially see antigen presented by self rather than by foreign MHC molecules^7–9, and autoreactive T lymphocytes are deleted¹⁰. Thus, the peripheral T-lymphocyte repertoire is skewed towards recogni-tion of antigen in the context of self-MHC and towards tolerance to self-antigens. During T-lymphocyte development in the thymus, this repertoire is formed by the interaction of TCR with MHC molecules resulting in positive and negative selection phenomena^7–10. Hybrid antibodies (HAbs) that carry binding sites to the TCR and to a surface marker on another cell can engage all T lymphocytes regardless of their specificity¹¹. It should be possible to mimic selection processes in normal animals with HAb that specifically link members of a TCR family to MHC molecules on the thymic stroma. We have probed T-lymphocyte development with HAbs linking V_β8 positive TCR to either class I or class II MHC products in thymic organ culture. Thymocytes exposed to either HAb in an early stage of maturation respond with a sig-nificant increase in the frequency of V_β8 carrying cells. At a later stage of development V_β8 positive thymocytes are depleted. These results illustrate the succession of positive and negative selection in the developing thymus of normal mice