Antigen Recognition by Cloned Cytotoxic T Lymphocytes

Antigen recognition by cytotoxic lymphocytes (CTL) 1 and by helper T cells is restricted by gene products of the major histocompatibility complex (MHC), called H-2 in the mouse (1). CTL recognize antigens in the context of Kand D-regionencoded structures, whereas helper T cells recognize antigen in the context of I-regionencoded structures. This H-2 restriction appears to be very tight: C T L specific for a conventional antigen X (e.g., a viral or minor histocompatibility [minor H] antigen) plus one H-2 haplotype will not lyse target cells expressing antigen X in the context of a different H-2 haplotype. Two types of models have been proposed to explain this phenomenon. According to the altered-self hypothesis (2), one T cell receptor recognizes neither the H-2-restricting element nor the conventional antigen X by itself but an interaction antigen formed by X and self-H-2 in physical proximity. On the other hand, dual-recognition models (3-5) postulate two types of receptors on every T cell, one, the anti-self-receptor, specific for the restricting element, the other specific for conventional antigen X. Recently, support for this latter view has been drawn from experiments with chimeric mice where it was demonstrated that the mature T cell repertoire is preferentially restricted by those H-2 antigens expressed on radioresistant cells present during T cell ontogeny (3, 6). Thus, bone marrow stem cells from H-2 heterozygous (A × B)F1 mice give rise to a predominantly Aor B-restricted T cell receptor repertoire, depending on the H-2 type (A or B) of the thymus in which the Fl-derived stem cells mature (3, 7). The selection for self-H-2-restricted T cells is, indeed, more easily understood in terms of a selection for ceils with anti-self receptors. However, the nonabsolute nature of self-H-2 learning (6-10), and the presence of T ceils restricted to foreign H-2 antigens in normal (11, 12) and neonatally tolerant mice (13) did leave room for one-receptor theories: In terms of the altered-self hypothesis, T cells that recognize self-H-2 plus X might be cross-reactive with allo-H2 plus Y, i.e., the same interaction antigen may be formed in different ways. Such cross-reactivity has been referred to as "aberrant recognition" by Doherty and * Supported by grants AI-14269 and CA-14501 from the U. S. Public Health Service. :~ Recipient of a fellowship from the Deutsche Forschungsgemeinschaft. Present address is the Institute fffir Virologie und Immunobiologie der Univesit~it Wiirzburg, Versbacher Landstrasse 7, D-8700 Wiirzburg, Federal Republic of Germany. 1Abbreviations used in this paper: CASUP, concanavalin A-induced spleen cell supernatant; Con A, concanavalin A; CTL, cytotoxic T lymphocytes; LPS, lipolysaccharide; MHC, major histocompatibility complex; MLC, mixed lymphocyte cultures; TNP, trinitrophenyl; TNP-BSA, trinitrophenylated bovine serum albumin.