1-12 Lymphocytes activated by antigen give rise to clones of antigen-specific effector cells that mediate adaptive immunity.
There are two critical features of lymphocyte development that distinguish adaptive immunity from innate immunity. First, the process described above that assembles antigen receptors from incomplete gene segments is carried out in a manner that ensures that each developing lymphocyte expresses only one receptor specificity. Whereas the cells of the innate immune system express many different pattern recognition receptors and recognize features shared by many pathogens, the antigen-receptor expression of lymphocytes is ‘clonal,’ so that each mature lymphocyte differs from others in the specificity of its antigen receptor. Second, because the gene rearrangement process irreversibly changes the lymphocyte’s DNA, all its progeny inherit the same receptor specificity. Because this specificity is inherited by a cell’s progeny, the proliferation of an individual lymphocyte forms a clone of cells with identical antigen receptors.
There are lymphocytes of at least 108 different specificities in an individual human at any one time, comprising the lymphocyte receptor repertoire of the individual. These lymphocytes are continually undergoing a process similar to natural selection: only those lymphocytes that encounter an antigen to which their receptor binds will be activated to proliferate and differentiate into effector cells. This selective mechanism was first proposed in the 1950s by Macfarlane Burnet, who postulated the preexistence in the body of many different potential antibody-producing cells, each displaying on its surface a membrane-bound version of the antibody that served as a receptor for the antigen. On binding antigen, the cell is activated to divide and to produce many identical progeny, a process known as clonal expansion; this clone of identical cells can now secrete clonotypic antibodies with a specificity identical to that of the surface receptor that first triggered activation and clonal expansion (Fig. 1.16). Burnet called this the clonal selection theory
A single progenitor cell gives rise to a large number of lymphocytes, each with a different speciÿcity
Fig. 1.16 Clonal selection. each lymphoid progenitor gives rise to a large number of lymphocytes, each bearing a distinct antigen receptor. lymphocytes with receptors that bind ubiquitous self antigens are eliminated before they become fully mature, ensuring tolerance to such self antigens. When a foreign antigen (red dot) interacts with the receptor on a mature naive lymphocyte, that cell is activated and starts to divide. It gives rise to a clone of identical progeny, all of whose receptors bind the same antigen. Antigen specificity is thus maintained as the progeny proliferate and differentiate into effector cells. once antigen has been eliminated by these effector cells, the immune response ceases, although some lymphocytes are retained to mediate immunological memory.
Each lymphocyte bears a single type of receptor with a unique speciÿcity
Interaction between a foreign molecule and a lymphocyte receptor capable of binding that molecule with high afÿnity leads to lymphocyte activation
The differentiated effector cells derived from an activated lymphocyte will bear receptors of identical speciÿcity to those of the parental cell from which that lymphocyte was derived
Lymphocytes bearing receptors speciÿc for ubiquitous self molecules are deleted at an early stage in lymphoid cell development and are therefore absent from the repertoire of mature lymphocytes
Fig. 1.17 The four basic principles of clonal selection.
of antibody production; its four basic postulates are listed in Fig. 1.17. Clonal selection of lymphocytes is the single most important principle in adaptive immunity.
1-13 Lymphocytes with self-reactive receptors are normally eliminated during development or are functionally inactivated.