The T cell receptor puzzle

Abstract

As long as this was possible, Jerne was a firm believer in the notion that antibodies are the sole molecular basis of immunological specificity and of idiotypic network interactions1,2. In defending this notion, he had to deal with recalcitrant implications derived from the genetic control of immune responsiveness, notably the growing evidence that essentially all Ir genes were found to map to the MHC. Since Ir genes controlled the responsiveness of T cells in an antigen-specific fashion, what was more plausible than to propose that the antigen receptors of T cells were the direct products of these Ir genes, and thus of genes linked to the MHC? These ideas were put forward by prominent immunologists including Hugh McDevitt and Baruj Benacerraf, both pioneers in studies of Ir genes3. Since antibody genes were definitely not linked to the MHC, notably Benacerraf and coworkers suggested that T cell antigen receptors, on cells and in secreted form, were different from immunoglobulins and represented another, second class of antigen-specific receptors in the immune system3–5. A fundamental difference between the receptors of T cells and antibodies was further supported by experiments showing that T cells recognized protein antigens differently from antibodies and B cells. Whereas B cells reacted to conformational epitopes that were destroyed by denaturing the protein, T cells reacted to sequential epitopes that were resistant to denaturation.