Ruth Epstein

T-cell inhibition of humoral responsiveness: II. Theory on the role of restrictive recognition in immune regulation

Abstract A general theory is presented which deals with the finding that effector T-cell inhibitory and cytotoxic activity are K/D-restricted whereas effector T-cell cooperating activity and delayed-hypersensitivity are I-restricted. It is argued that this fact alone requires the T-cell receptor to be dual-recognative. Within the framework of the associative recognition (“two-signal”) theory, a dual-recognition model of restrictive recognition is proposed. The questions dealt with derive from our previous study (1): (1) Under what conditions may effector T-cell function be unrestricted? (2) Are paralysis and induction of antigen-sensitive t-cells restricted? (3) What determines restrictive specificity and the relationship between restriction and T-cell function? (4) What are the expected characteristics of the germ-line genes which encode the T-cell receptor? The elements of the minimal model are: (1) The T-cell expresses a receptor consisting of an anti-self MHC (S) site and an anti-antigen (X) site physically linked to each other and to a signal donor site. (2) The target cell has on its surface the antigenic determinant, X, and the restricting element, S(K/D or I), linked to a signal acceptor site. (3) Restricted signaling requires (a) an interaction between X and anti-X and (b) the positioning of the acceptor with respect to the donor, i.e. formation of a “synapse,” by an interaction between S and anti-S. (4) The acceptor linked to K/D can read inhibitory and cytotoxic signals whereas the acceptor linked to I can read cooperative and delayed-hypersensitivity signals. (5) The paralysis and induction of antigen-sensitive t-cells can be unrestricted (the anti-S site of the t-cell need not be occupied). All signals to the t-cell are initiated uniquely by the X-anti-X interaction. (6) Positive selection in the thymus via an S anti-S interaction between a pre-t-cell expressing anti-S with a “restricting cell,” expressing S, fixes the specificity of restrictive recognition as well as the appropriate effector function. (7) Proposition: The t-cell receptor is H-2 encoded. The data presented earlier (1, 14) as well as the competing Janeway-Binz-Wigzell dual-recognition model (59) are analyzed.

Independence of θ and TL surface antigens and killing by thymidine, cortisol, phytohemagglutinin, and cyclic AMP in a murine lymphoma

Summary Thymic like lymphomas bear θ antigen and often TL antigen, and are killed by low concentrations of corticosteroids. These lymphomas are also very sensitive to killing by phytohemagglutinin and thymidine, in contrast to myelomas. Since θ and TL antigens and sensitivity to steroids and phytohemagglutinin change during the maturation of thymus cells to immunocompetent lymphocytes, these properties were studied in lymphoma variants. Variants selected for loss of detectable θ antigen or sensitivity to hydrocortisone, phytohemagglutinin, thymidine, thioguanine, or cyclic AMP still retain the unselected markers. This suggests that, although thymocyte properties appear to be coordinately regulated during differentiation, the expression of each may be altered by a separate mechanism.

T-cell inhibition of humoral responsiveness. I. Experimental evidence for restriction by the K- and/or D-end of the H-2 gene complex.

Abstract The inhibition (“suppression”) of an in vitro antibody response to SRBC by T-cells with specificity for histocompatibility antigens, is H-2 K/D-restricted whether or not the target determinant is H-2 I-region or non-H-2 encoded. By contrast, cytotoxic T-cells specific for histocompatibility antigens mediate a lysis of targets that is K/D-restricted in all cases except one: when the target determinant is H-2 I-region encoded, lysis is unrestricted. Further, it is shown that the target determinant and the restricting element must be on the same cell for effector function to be mediated. A spleen population immunized with histocompatibility antigens contains inhibitory and cytotoxic T-cells separable when I-region encoded determinants are the target. Thus, we conclude that the cytotoxic T-cell does not function as an inhibitory T-cell and vice versa . If the findings with this model experimental system may be extrapolated to the regulation of normal in vivo immune responsiveness then two K/D-restricted separable T-cell populations must mediate cytotoxicity and inhibition of humoral responsiveness. This finding, that with I-region encoded targets only, inhibitory T-cells are K/D-restricted whereas cytotoxic T-cells are not, raises questions about the mechanism of restrictive recognition which are dealt with in the context of the “two signal” model.