In contrast, lymphocytes with strongly self-reactive receptors must be eliminated to prevent autoimmune reactions; this process of negative selection is one of the ways in which the immune system is made self-tolerant. The default fate of developing lymphocytes, in the absence of any signal being received from the receptor, is death by apoptosis, and as we will see, the vast
Development of B lymphocytes. Development of T lymphocytes. Positive and negative selection of
T cells.
Fig. 8.1 B cells develop in the bone marrow and migrate to peripheral lymphoid organs, where they can be activated by antigens. In the first phase of development, progenitor B cells in the bone marrow rearrange their immunoglobulin genes. This phase is independent of antigen but is dependent on interactions with bone marrow stromal cells (first panels). It ends in an immature B cell that carries an antigen receptor in the form of cell-surface IgM (second panels), and in the second phase it can now interact with antigens in its environment. Immature B cells that are strongly stimulated by antigen at this stage either die or are inactivated in a process of negative selection, thus removing many self-reactive B cells from the repertoire. In the third phase of development, the surviving immature B cells emerge into the periphery and mature to express IgD as well as IgM. They can now be activated by encounter with their specific foreign antigen in a peripheral lymphoid organ (third panels). Activated B cells proliferate, and differentiate into antibody-secreting plasma cells and long-lived memory cells (fourth panels).
majority of developing lymphocytes die before emerging from the central lymphoid organs or before completing maturation in the peripheral lymphoid organs.
In this chapter we describe the different stages of the development of B cells and T cells in mice and humans from the uncommitted stem cell in the bone marrow up to the mature, functionally specialized lymphocyte with its unique antigen receptor ready to respond to a foreign antigen. The final stages in the life history of a mature lymphocyte, in which an encounter with its antigen activates it to become an effector or memory lymphocyte, are discussed in Chapters 9–11. We now know that the Band T-cell development that predominates during late fetal life and after birth is distinct from waves of lymphocyte development that take place earlier in fetal ontogeny. These earlier waves originate from stem cells found in the fetal liver and in even more primitive hematopoietic tissues in the developing embryo. Unlike the lymphocytes that develop from bone marrow stem cells, B and T cells that develop from these early fetal progenitors generally populate mucosal and epithelial tissues and function in innate immune responses. In the adult, these subsets of lymphocytes are minority populations in secondary lymphoid tissues. This chapter will focus on B and T cells that develop from bone marrow stem cells and that comprise the cells of the adaptive immune response (see Figs 1.7 and 1.20). The chapter is divided into three parts. The first two describe B-cell and T-cell development, respectively. In the third section, we discuss the positive and negative selection of T cells in the thymus.
Development of B lymphocytes.
The main phases of a B lymphocyte’s life history are shown in Fig. 8.1. The stages in both B-cell and T-cell development are defined mainly by the successive steps in the assembly and expression of functional antigen-receptor genes.
Generation of B-cell receptors in the bone marrow Negative selection in the bone marrow
Migration of B cells through the circulatory system to lymphoid organs and B-cell activation