Staphylococcal Enterotoxin B Induced Clonal Anergy in αβ T Cell Receptor Transgenic Mice

Superantigens such as staphylococcal enterotoxin B (SEB) have been widely used to study T cell tolerance. While both clonal deletion and apparent anergy have been described in response to superantigens, it has not been clear whether true anergy occurs, or whether the most reactive T cells are selectively deleted, leaving less reactive clones. To address this question, the response of an essentially monoclonal population of primary T cells to a superantigen was followed by priming ovalbumin (OVA) specific (X� T cell receptor transgenic mice with SEB. Cells from these mice appeared to be anergic in that they were hyporesponsive to OVA peptide as well as to SEB. The anergic cells could respond to PMA and ionomycin suggesting that a proximal signal transduction step was affected. Cells from transgenic mice primed with OVA peptide, the specific antigen, were not anergic. Thus, in this system, the ability to tolerize mature T cells appears to be a property unique to superantigens. To address the question of whether superantigen induced tolerance was due to T cell activation in the absence of costimulation, we examined the effect of the CD28/B7 pathway on the response of T cells to SEB and OVA. The T cell response to both OVA and SEB was enhanced by antibodies to the CD28 coreceptor suggesting that CD28/B7 mediated costimulation plays a role in the signal transduction pathways coupled to the two types of antigens. Chapter 1.1 (Introduction) The variable region of T cell receptor is made up from the products of five gene segments from the variable (V), diversity (D), and joining (J) gene families; Va. and Ja. make up the a. chain, whereas V�, D�, and J�, contribute to the � chain (reviewed in 1). Each chain is generated by the random rearrangement of these non contiguous gene segments (1). Because this is a random process, there is nothing to prevent the generation of T cells with receptors specific for self antigens. Tolerance can be defined as the process by which potentially self reactive lymphocytes are silenced. There have been three major hypotheses proposed to explain how the immune system aquires tolerance to self antigen. They are as follows: 1. Clonal deletion. This theory was first proposed by Lederberg (2) as a modification of Burnet's clonal selection theory (3). The theory proposed that immature cells react differently from mature lymphocytes in response to the engagement of their receptors: immature cells would be deleted whereas mature cells are activated. Thus lymphocytes with self reactive receptors would eventually come into contact with self antigen as they developed and this would result in their selective deletion. 2. Clonal anergy. In this view, self reactive cells were not physically eliminated. Instead they were functionally inactivated or anergized. Evidence for this hypothesis came from studies demonstrating that B cells in fetal mice could be tolerized without being physically deleted (4). 3. Suppression. This hypothesis suggested that self reactive lymphocytes were held in check by suppressor cells or suppressor factors. This hypothesis was supported by experiments showing that when lymphocytes from animals tolerized to a given antigen were transferred into naive animals,they prevented the hosts' lymphocytes from reacting to the tolerizing antigen (5,6).