Peter A. Bretscher

1) Induction of humoral antibody formation involves the obligatory recognition of two determinants on an antigen, one by the receptor antibody of the antigen-sensitive cell and the other by carrier antibody (associative interaction). 2) Paralysis of antibody formation involves the obligatory recognition of only one determinant by the receptor antibody of the antigen-sensitive cell; that is, a nonimmunogenic molecule (a hapten) can paralyze antigen-sensitive cells. 3) There is competition between paralysis and induction at the level of the antigen-sensitive cell. 4) The mechanisms of low- and high-zone paralysis, and maintenance of the unresponsive state, are identical. 5) High-zone paralysis occurs when both the carrier antibody and the receptor antibody are saturated, so that associated interactions cannot take place. 6) The mechanisms of paralysis and induction for the carrier-antigen-sensitive cell are identical to those for the humoral-antigen-sensitive cell. 7) The formation of carrier-antigen-sensitive cells is thymus-dependent, whereas humoral-antigen-sensitive cells are derived from bone marrow. Since carrier antibody is required for induction, all antigens are thymus-dependent. 8) The interaction of antigen with the receptor antibody on an antigen-sensitive cell results in a conformational change in an invariant region of the receptor and consequently paralyzes the cell. As the receptor is probably identical to the induced antibody, all antibody molecules are expected to be able to undergo a conformational change on binding a hapten. The obligatory associated recognition by way of carrier antibody (inductive signal) involves a conformational change in the carrier antibody, leading to a second signal to the antigen-sensitive cell. 9) The foregoing requirements provide an explanation for self-nonself discrimination. Tolerance to self-antigens involves a specific deletion in the activity of both the humoral- and the carrier-antigen-sensitive cells.

Cell-mediated, but not antibody-mediated, immune responses protect humans against certain pathogens that produce chronic diseases such as leishmaniasis. Effective vaccination against such pathogens must therefore produce an immunological "imprint" so that stable, cell-mediated immunity is induced in all individuals after natural infection. BALB/c mice "innately susceptible" to Leishmania major produce antibodies after substantial infection. In the present study, "susceptible" mice injected with a small number of parasites mounted a cell-mediated response and acquired resistance to a larger, normally pathogenic, challenge. This vaccination strategy may be applicable in diseases in which protection is dependent on cell-mediated immunity.

I present here a new model for the primary activation of precursor helper T cells. Observations demonstrate that the immune system learns not to respond to extrathymic, organ-specific self-antigens because of their early appearance in development. The immune system thus discriminates between peripheral self-antigens and foreign antigens and, when mature, usually makes an immune response against only the latter. Contemporary models for the activation and inactivation of T helper (Th) function do not account for such discrimination. The model proposed here is consistent with contemporary findings and incorporates a mechanism of peripheral self-nonself discrimination.