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How the Immune System Works to Protect the Host from Infection
Summary: Charles Janeway worked on several areas of immunology: T cell development, B cell development, and the regulation of the immune response.
The immune system can be thought of as a sensory system for pathogens; that is its primary job. It detects these pathogens by signaling their presence via a very ancient system of host defense, involving elements that are as old as the oldest multicellular organisms. This system—called innate immunity—is found in plants, invertebrates, and vertebrates. It responds to pathogen challenge by means of an ancient recognition system that we call pattern recognition. We call it this because it recognizes microbe-associated molecular patterns. These are essential elements of bacterial pathogenesis, such as the lipopolysaccharide (LPS) found in the coats of gram-negative bacteria. Without LPS, such bacteria would be harmless. At least four patterns are known to exist: LPS; the lipoteichoic acids found in gram-stain-positive bacterial cell walls; the DNA characteristic of bacteria, so-called CpG DNA; and double-stranded RNA, a signature of viruses. Each of these is recognized by sentinels on the surface of phagocytes found all over the body. Thus the innate immune system can react almost immediately to these and presumably to other microbes as well.
The recognition event triggers the expression of molecules that are required for an adaptive immune response by naive T lymphocytes. These molecules, called costimulatory molecules, are one component of what is needed to generate adaptive immunity. The other is a specific peptide:MHC (major histocompatibility complex) ligand for the receptors found on all T lymphocytes. The BCR, a receptor on B lymphocytes, is also present in enormous variety. These receptors are encoded in germline gene segments and do not form receptors until they are acted upon by enzymes discovered by David Schatz (HHMI, Yale University). These are the only site-specific recombinases known in vertebrates and are made up of the RAG1 and RAG2 proteins. They act upon short stretches of DNA that lie 3' of the V (variable) gene segments and 5' of the D (diversity) or J (joining) gene segments. Only when the gene segments are assembled into a complete variable-region exon can an antibody or T cell receptor be formed and put on the cell surface. Our lab studies the surface receptors of lymphocytes, their development, and their activation. We have come to the startling conclusion that the adaptive immune system is referential to self, in that both the T lymphocytes and the B lymphocytes have to recognize internal ligands to be selected and to survive.
Moreover, we have recent evidence that the ability to respond to challenge with antigen involves self-ligands as well as foreign ligands. The reason for this is not entirely clear, but we believe that it has to do with signaling via the TCR and the BCR, which needs to be intermittently bound to keep these cells viable; without these signals, the lymphocytes die. We are still at work on this model of immune system function, but it includes a set of cells that regulates the activity of cells that attack host tissues, recently described by our lab and several others. These cells are almost certainly conventional T cells that make unconventional cytokines when they encounter self-antigens.
Thus my concept of the adaptive immune system, which allows effective vaccination to proceed, is more complex than the simple clonal selection theory of Burnet and Medawar, which has been the dominant paradigm of immunology for nearly 50 years. It also accommodates the Jerne network hypothesis, in which Niels Jerne proposed that the B cell system is interconnected though soluble immunoglobulin molecules that interact with the BCR. Our studies have provided the first real evidence that this idea is correct and has a function in maintaining the B cell receptor repertoire. By bringing together these three ideas—the role of the innate immune system in setting up the adaptive immune response, the role of the adaptive immune system being to compare internal with external images of the immunological universe, and the role of T cells as regulators of the activity of other T cells—we have synthesized the main threads of immunological theory into a simple and satisfying whole.
This work was supported in part by the National Institutes of Health.
Last updated April 15, 2003
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