Helper T (Tn) lymphocytes are involved in the pathogenesis of a number of human and experimental autoimmune diseases. Normally these cells play a central role in control of the immune system (Schwartz, 1986). On recognition of foreign antigens associated with class II molecules of the major histocompatibility complex (MHC), Tn cells produce a range of lymphokines with extensive effects on other cells of the immune system (Figure 1). However, in rare cases, TH cells can recognize self-antigens, augment some of the interactions depicted in Figure 1, and ultimately bring about tissue damage. In this review, we will discuss how recent advances in our understanding of both T cell recognition and immunological tolerance to self-antigens have affected our perception of autoimmune disease. Arising from this discussion, we will describe several potential targets for immune intervention, most notably the predisposing MHC molecules, the T cell receptor, and the self-antigen or target of the autoimmune process.

T Cell Recognition The minimal requirement for activation of Tn cells is the occupation of their T cell receptors (TCR) by a complex formed between fragments of antigen and class II MHC molecules. Class II molecules are encoded by IA and IE genes of the H-2 complex in mice and DR DQ, and DR genes of the HLA complex in man. In addition to this molecular triad, accessory (cell differentiation) molecules on the surface of the T cell (CD4 for Tn and CD8 for cytotoxic T (Tc) cells) interact with MHC molecules on the surface of the antigen-presenting cell (APC), increase the overall affinity of cell-cell contact, and permit recognition of the antigen-MHC complex by low affinity TCR. The majority of antigens for T cells are recognized in a denatured or fragmented form (Moller, 1987). This requirement presumably allows for association of fragments with the antigen-binding “cleft” of class I (Bjorkman et al., 1987) and the predicted “cleft” of class II MHC molecules (Brown et al., 1988). The majority of polymorphic MHC residues are clustered around this “cleft,” and this indicates how these residues directly influence antigen binding and interaction with TCR (Bjorkman et al., 1987). The immune system can respond to a wide variety of different protein antigens, and this implies that any one