CLONAL DELETION IN NONRESPONSIVENESS TABLE I Mouse

Recent analyses of immune response (It) 1 gene-con t ro l l ed responses have led to the conclusion that nonresponsiveness, in the major i ty , if not all, of the cases, is caused by the absence of funct ional T cell clones ra ther than a failure of an t igen presenta t ion (1-4). Theoret ica l ly , nonresponsiveness at the T cell level can arise in at least two ways, bo th associated with the ind iv idua l iza t ion of the T cell repertoire. First, some T cell clones are physical ly or funct ional ly e l imina ted because they react wi th selfmajor h i s tocompat ib i l i ty complex (MHC) antigens, or wi th o ther self ant igens in association with self M H C molecules (5). Second, the T cell repertoire is posit ively selected to recognize self M H C molecules or o ther self-antigens in the context of selfM H C molecules, and therefore the clones recognizing foreign ant igens that are not ident ical wi th or closely re la ted to self ant igens are not inc luded in the reper toire (6). To test whether a case can be made for the involvement of one of these two mechanisms in nonresponsiveness, we have used as a model system the secondary in vitro response of T cells deple ted of a l loreact ive cells to ant igens presented by al logeneic ant igen-present ing cells (APC) (1). In previous exper iments test ing the responses to three different ant igens [poly(glu4°ala6°), poly(glu~llysa4tyr 1~) (GLT), and lacta te dehydrogenase B] in a large n u m b e r of al logeneic T ce l I -APC combina t ions , we have not found a single case of nonresponsiveness (1, 2, 4). Fur thermore , we have demons t ra ted that these responses are restr icted by bo th A(A,~AB) and E(E,,E/~) molecules, when the APC express both molecules, and only by the A molecule when the APC do not express cell-surface E molecules (7). The only except ion in this pa t t e rn was the response of al logeneic (H-2 a) T cells to G L T presented by APC expressing both A k and E k molecules, which was channel led selectively th rough the A k molecules (7). Thus, al logeneic T cells d id not a p p e a r to recognize G L T in the context of E k molecules. Using H-2recombinan t strains that differ from each other only in terms of expression vs. nonexpression of cell-surface E molecules, we demon-