Integrating Cellular Specificity and Genetic Control of the Immune System

The immune system provides a remarkably powerful defense against many microbes. The tragic consequences of immune deficiency are now all too familiar-in the large number of infections, finally lethal, that occur in patients with AIDS and in the tragic outcomes seen in humans born without functioning immune systems. On the other hand, the power of the marshalled immune system is formidable. Aggressive programs of vaccination have eliminated smallpox from the face of the globe; poliomyelitis has been eradicated from the Western Hemisphere.

For a young physician, such as I was in the early 1960s, understanding how it was possible for the immune system to mount its vast array of highly specific responses and how such responses would result in deploying the body's mechanisms for eliminating pathogens was an exciting challenge. By the time I entered the field, a distinction between cellular immunity, now known to be mediated by T cells, and antibody responses was clear. What was particularly challenging was to understand the nature of the T-cell receptor and of the antigens that it recognizes.

I was fortunate to be a postdoctoral fellow in the laboratory of one of the true innovators in our field, Baruj Benacerraf, who was then doing the work that would lead to his receipt of the Nobel Prize in Physiology or Medicine in 1980. In Baruj's laboratory at New York University School of Medicine, two apparently unrelated projects were underway. I was working on the cellular immunity problem, while my good friend and long-time colleague, Ira Green, was studying the genetic control of immunity. We often worked jointly and began to form the view that the two fields might be intimately related.

Ira and I, and our gifted younger colleague, Ethan Shevach, formed the view that there must be a direct link between what we had learned about the specificity of cellular immunity and how the "immune response" (Ir) genes acted. We knew the predominant Ir genes mapped into the major histocompatibility complex of genes and that they were tightly linked to genes coding for a newly recognized set of MHC molecules, now designated the class MHC-I molecules. We reasoned that the class II molecules themselves might directly participate in the antigen-recognition process and that antibodies to them might therefore block T-cell recognition of antigen. We tested this hypothesis using two strains of guinea pigs with known antigen responses. We showed that there was a direct association between the class II molecules and the antigen and that class II molecules did not contribute to the receptor itself.

Indeed, the future of immunology will rest almost certainly on the sophisticated combination of knowledge of T-cell specificity and of how the system regulates itself. My own modest hopes to work at the interface of science and medicine have proved to be a continuously exciting undertaking. They have brought me to my current dual roles of leading a research group and having responsibility for leadership in the U.S. AIDS research effort as the Director of the NIH Office of AIDS Research. The challenge now is whether the insights gained from fundamental research in immunology can make the expected contribution to preventing and controlling HIV infection.