When Burnet formulated his theory, nothing was known of the antigen receptors or indeed the function of lymphocytes themselves. In the early 1960s, James Gowans discovered that removal of the small lymphocytes from rats resulted in the loss of all known adaptive immune responses, which were restored when the small lymphocytes were replaced. This led to the realization that lymphocytes must be the units of clonal selection, and their biology became the focus of the new field of cellular immunology.
Clonal selection of lymphocytes with diverse receptors elegantly explained adaptive immunity, but it raised one significant conceptual problem. With so many different antigen receptors being generated randomly during the lifetime of an individual, there is a possibility that some receptors might react against an individual’s own self antigens. How are lymphocytes prevented from recognizing native antigens on the tissues of the body and attacking them? Ray Owen had shown in the late 1940s that genetically different twin calves with a common placenta, and thus a shared placental blood circulation, were immunologically unresponsive, or tolerant, to one another’s tissues. Peter Medawar then showed in 1953 that exposure to foreign tissues during embryonic development caused mice to become immunologically tolerant to these tissues. Burnet proposed that developing lymphocytes that are potentially self-reactive are removed before they can mature, a process known as clonal deletion. Medawar and Burnet shared the 1960 Nobel Prize for their work on tolerance. This process was demonstrated to occur experimentally in the late 1980s. Some lymphocytes that receive either too much or too little signal through their antigen receptor during development are eliminated by a form of cell suicide called apoptosis—derived from a Greek word meaning the falling of leaves from trees— or programmed cell death. Other types of mechanisms of immunological tolerance have been identified since then that rely on the induction of an inactive state, called anergy, as well as mechanisms of active suppression of self-reactive lymphocytes. Chapter 8 will describe lymphocyte development and tolerance mechanisms that shape the lymphocyte receptor repertoire. Chapters 14 and 15 will discuss how immune tolerance mechanisms can sometimes fail.
Principles of adaptive immunity.
1-14 Lymphocytes mature in the bone marrow or the thymus and then congregate in lymphoid tissues throughout the body.
Lymphocytes circulate in the blood and the lymph and are also found in large numbers in lymphoid tissues or lymphoid organs, which are organized aggregates of lymphocytes in a framework of nonlymphoid cells. Lymphoid organs can be divided broadly into the central or primary lymphoid organs, where lymphocytes are generated, and the peripheral or secondary lymphoid organs, where mature naive lymphocytes are maintained and adaptive immune responses are initiated. The central lymphoid organs are the bone marrow and the thymus, an organ in the upper chest. The peripheral lymphoid organs comprise the lymph nodes, the spleen, and the mucosal lymphoid tissues of the gut, the nasal and respiratory tract, the urogenital tract, and other mucosa. The locations of the main lymphoid tissues are shown schematically in Fig. 1.18; we describe the individual peripheral lymphoid organs in more detail later in the chapter. Lymph nodes are interconnected by a system of lymphatic vessels, which drain extracellular fluid from tissues, carry it through the lymph nodes, and deposit it back into the blood.