Activation of help and contrasuppression as essential prerequisites for immune response

The network theory proposes the immune system as a self-centered defense mechanism, which continuously maintains a steady state of activity via idiotypic-anti-idiotypic interactions. In line with this hypothesis, the steady state of the immune system has been described to represent a status of suppressed activity, response being manifested by release from suppression. There is evidence that release from suppression is initiated by activation of contrasuppressor cells (TCS), which either transfer a state of resistance towards suppression on helper T-cells (TH) or interact directly with suppressor T-cells (TS). In the latter case, it was postulated that the nominal antigen of contrasuppressor T-cells are antibodies and that TS and TCS interact one with the other via idiotypic-anti-idiotypic structures. The present report examined the role of TCS in initiation of response and proved that the responding state requires activation of TH as well as TCS. While antigenic stimulation (TNP) resulted in concomitant activation of TH and TCS, it was possible to dissect these two prerequisites for response by application of a monoclonal anti-TNP antibody (AB) carrying a recurrent idiotype (Sp6) followed by application of a subimmunogenic dose of the nominal antigen. Clonal analysis of regulatory cells via limiting dilution (LD) cultures revealed that a subimmunogenic dose of antigen led to activation of help but failed to activate TCS. On the other hand application of AB, which did not initiate response, resulted in activation of TCS, but not in activation of TH, i.e., these were not released from suppression. However, consecutive activation of TCS via AB and of help via a subimmunogenic dose of antigen moved the immune system into the responding state. Activation of TCS via AB was found to be independent from the mode of application, i.e., free AB, AB coupled to syngeneic cells, or AB coupled to the nominal antigen, although most straightforward results were obtained with free AB, since syngeneic cells exerted an additional suppressive effect, and AB-antigen (TNP) conjugates activated TNP-specific TH as well as TCS. Furthermore, AB-induced activation of TCS was independent of the recipient's age. Yet, the effect was most pronounced when AB were applied neonatally, i.e., after a hyporesponsive stage, animals were hyperreactive towards the nominal antigen, and this hyperreactivity was initiated by expansion of TCS. This extends the notion of high idiotypic connectivity in the neonatal period to the level of regulatory T-cells.(ABSTRACT TRUNCATED AT 400 WORDS)