The influence of thymus on the development of MHC restrictions exhibited by T-helper cells

Abstract

IMMUNE functions depend largely on the activities of peripheral lymphocytes which have been ‘processed’ in the thymus (T cells). The best characterised activities of these cells, such as in vitro cytotoxicity and suppressor and helper capacities in adoptive immunisations seem to be mediated by distinct subpopulations. However, it has emerged that T cells of all subpopulations exhibit a dual recognition faculty, on the one hand, towards entities coded by the major histocompatibility gene complex (MHC). and on the other towards foreign antigens. Without appropriate MHC recognition ‘foreignness’ may not be noticed, giving rise in various functional assays to what has been termed MHC restriction. For example, in the mouse, T cells may lack cytotoxicity unless they have H–2 region gene products¹, in common with their target cells. T cells which ‘help’ in antibody responses can only do so fully if the B cells with which they are cooperating have similar I-region coding². These various restrictions were thought to represent the need for interaction of like substances on cell surfaces perhaps to establish propinquity before any subsequent interactions could be initiated. Recently, however, it has been demonstrated^3,4 that irradiated bone marrow chimaeras of the type A + B → (A × B)F₁ possessed populations of T cells of A and B origin each of which was capable of interacting with B-cell populations of both A and B origin (A and B are used here purely as symbols for MHC-disparate mouse strains). Thus it seemed whatever the genetic determinacy of the cell, it could, when appropriately conditioned, establish reactions based on identity with either genetically similar or genetically different cells^2,5. The exact nature of this conditioning began to emerge from experiments of Bevan⁶ and Zinkernagel⁷ who found that T cells from (A × B)F₁ → A chimaeras could only kill target cells bearing A type MHC determinants, whilst no cytotoxicity towards B targets was possible. Comparable studies gave analogous results for helper T cells^8,9 and recently, it was shown that the events which seem to determine the pattern of H–2 restricted specifities of the T cells concerned with cytotoxicity occur within the thymus gland⁷. We now show that intrathymic conditioning also determines the restriction specificities of T cells involved in helping antibody production.