Adam Lowy

Molecular signals in antigen presentation. I. Effects of interleukin 1 and 2 on radiation-treated antigen-presenting cells in vivo and in vitro.

In order to clarify the nature of the defect in the process of antigen presentation caused by uv radiation, low-density spleen cells were used as a potent APC source in a hapten-specific cytolytic T-cell (Tc) system. It was demonstrated that IA+ weakly adherent low-density spleen cells, when directly coupled with azobenzene arsonate (ABA), led to the activation ABA-specific Tc. When these APC were exposed to uv radiation (12 J/m2/sec) for 30 sec, their ability to lead to Tc activation was markedly inhibited. The defect imposed by uv radiation could be specifically bypassed by the addition of small amounts of homogeneous IL-1 or IL-2. This led to the specific activation of ABA-reactive H-2-restricted Tc. The purified IL-1 was also found to bypass the systemic defect imposed in vivo by external uv radiation of mice. This may indicate a potential therapeutic role for IL-1.

Studies of immune responsiveness and unresponsiveness to the p-azobenzenearsonate (ABA) hapten.

Despite years of study, characterization of the signals and cellular receptors critical to the regulation of immune responses remains unclear. It is well-established that populations of regulatory T cells exist which modulate the activity of various effector cells during an immune response. T helper cells, through the release of soluble mediators called lymphokines, exert potentiating influences on B cell and T cell responses to foreign antigen. Conversely, T suppressor cells exert an inhibiting effect on the immune system. Down regulation of the immune response is manifest as an induced state of decreased responsiveness to an otherwise immunogenic challenge. This is typified by two types of unresponsiveness: non-infectious or infectious tolerance (suppression). Non-infectious tolerance is the consequence of elimination or inactivation of clones of antigen-reactive cells in the absence of suppression (Nossal 1983). Suppression is an active process characterized by the ability to transfer unresponsiveness from one animal to another. The important elements in this transfer were first described by Gershon & Kondo (1971) to be T cells and were hence named suppressor T cells. In this review, we will discuss our results over the past 3 years concerning both infectious and non-infectious tolerance in the azobenzenearsonate (ABA) hapten system. The problems we have addressed during this time have concerned: 1) the association of Igh and I-J encoded determinants on suppressor hybridomaderived suppressor factors; 2) the relationship between Igh restriction and antigen specificity for suppressor factor-mediated suppression; 3) the role of differential

The Role of Idiotype in T-Cell Regulatory Events

In his original proposal of an immunoregulatory network of lymphocytes, Jerne proposed that the naive immune system is in a negatively regulated state.(1) Before the introduction of antigen, a lymphocyte specific for a certain antigenic determinant (epitope) is held in check by another lymphocyte’s anti-idiotypic receptor. In this network all antibodies represent anti-idiotypes. The appearance of antigen perturbs this homeostatic down-regulation and an immune response is generated. As a consequence of the immune response to the individual epitopes, the amount of antigen is reduced below a threshold level whereupon the systems returns to homeostasis. In recent years, the mechanism by which the immune response is regulated has been investigated. Antigen-specific(2) and nonspecific(3) T-suppressor (Ts) cells play a critical role in this regulation. Further, idiotype-anti-idiotype interactions may be important in both Ts—target cell and Ts—Ts interactions. However, rather than existing in a down-regulated state before the appearance of an antigen, the immune system can be thought of as a complex set of dynamically activated and regulated cellular elements. Antigen stimulates an immune response (postive) and then initiates immunoregulatory (negative) events, instead of simply perturbing homeostatic regulation. Differential antigen presentation to T-helper (Th) and Ts cells by specific antigen-presenting cells (APCs) may shift this delicate balance from immunity to immune regulation. It appears that presentation of antigen by an I-A+ I-J− APC activates Th(4) cells, while an I-J+ I-A− APC activates Ts cells.(5) Moreover, differential expression of I-A- or I-J- encoded molecules on APCs might mediate these processes. On the other hand, T-cell idiotypes may serve as cell interaction molecules in immunoregulatory events subsequent to Ts activation.(6)

Activation of suppressor cells is genetically restricted by the I-J Subregion

Evidence describing T cell-mediated suppression of T cell reactivities (1–4), humoral responses (5), and even other suppressor T (Ts) cells (6,7) suggests an important regulatory role for these cells. Manipulation of the Ts pathway may also have important clinical applications. For instance, in murine systems, altering suppressor signals has been shown to have an effect on: growth of a tumor challenge (8), development of experimental arthritis (9), encephalitis (10), as well as acceptance of allografts (11).