Affinity Maturation

Klaus Rajewsky, Institute for Genetics, University of Cologne, Weyertal 121, Koln, Germany

The changes of antibody quality in the course of the antibody response is a classical immunological phenomenon. One such change is the gradual increase of antibody affinity for the immunizing antigen with time, called affinity maturation. Affinity maturation is typical of, and regularly observed in, T cell-dependent responses and is a key feature of immunological memory in B cells. Upon secondary immunization with a T cell-dependent antigen an anamnestic antibody response is produced, consisting of antibodies with a higher affinity than that of primary response antibodies.

Burnet's clonal selection theory provided a theor etical framework for affinity maturation, as shown in Figure 1. The B cells in the peripheral B cell pool express a clonally distributed, diverse antibody repertoire. This repertoire includes antibody specificities against any given antigen or antigenic determinant, but, in general, high-affinity antibodies should be less frequent than antibodies of average or low affinity. The clonal selection theory postulates that antigen selectively expands B cells expressing antibodies on their surface to which it can bind. With decreasing antigen concentration in the course of the response this mechanism results in the preferential expansion of B cells expressing high-affinity antibodies, as depicted in the upper part of Figure 1. We have

Antigen

Peripheral 6 cell pool and /or

B cell death

Peripheral 6 cell pool and /or

B cell death

Generation and selection of high-affinity somatic mutants

Selection of rare, pre-existing high-affinity B cell clones

Generation and selection of high-affinity somatic mutants

Figure 1 Models of affinity maturation. (Taken, with modification, from Rajewsky K (1989) Progress in Immunology 7: 400.)

learned in the meantime that the process of B cell triggering is more complex: the B cell captures antigen by its receptor antibody from antigen-presenting (follicular dendritic) cells, processes it intracellularly and exposes fragments of the antigen on its surface, in the groove of major histocompatibility complex (MHC) antigens of class II. Subsequently, T helper cells recognize the antigen-loaded MHC molecules and signal the B cell into its pathway of proliferation and differentiation. This multistage process, together with the variability of antigenic valency, makes the relation of antibody affinity to cellular selection complicated (indeed selection seems sometimes driven by the on-rate of antigen binding rather than affinity), but does not change the picture in principle.

The model depicted in the upper part of Figure 1 is in line with experimental evidence that the B cell clones dominating secondary and hyperimmune responses to a given antigen often differ strikingly from those dominating the primary response in terms of antibody variable (V) region gene usage. However, it has become clear that the central mechanism of affinity maturation is not the selection of rare, preexisting high-affinity antibodies, but a process of somatic evolution, in which somatic antibody mutants are generated at high rate as a consequence of antigenic contact and high-affinity mutants subsequently selected by antigen (Figure 1, lower part). It is often forgotten that Burnet considered this possibility already in his clonal selection theory: 'The . . . postulate, that active sites on cell surface or globulin molecules can be modified to a wider reactivity by somatic mutation, provides the chief agent to allow change in antibody character as immunization proceeds. If the primary postulates of the clonal selection theory are accepted, such a result of somatic mutation is as much in order as any other'. The tools of molecular biology allowed this possibility to be studied directly, by isolating and sequencing anti body V genes expressed by B cells participating in model immune responses. Initially, the V genes were identified in hybridoma cells selected from various stages of the immune response. They can now be isolated from the overall B cell population or even single B cells by specific gene amplification, using the polymerase chain reaction. These experiments demonstrated that, within a short time after priming with a T cell-dependent antigen, the initial repertoire of germ line-encoded antibodies is completely changed into a repertoire of somatic antibody mutants as they are exclusively seen in secondary and hyperimmune responses. This is achieved by a mechanism introducing somatic point mutations into rearranged antibody genes at an exceedingly high rate, estimated to be in the range of 1 x 10" ' per base pair per generation. The mutations are introduced in a stepwise manner in the course of cellular proliferation and mutants expressing high affinity for the antigen are selected out in a highly efficient manner, preventing the accumulation of mutants expressing useless, potentially harmful (autoaggressive) specificities. Genetic engineering experiments have directly demonstrated that certain key mutations, often repeatedly seen in the repertoire of antibody mutants as it arises after immunization with a given antigen, are directly responsible for an increase of affinity for the antigen. However, because of the high rate of somatic mutation the antibodies also harbor a multitude of mutations which are not affinity selected (e.g. 'silent' exchanges). Affinity maturation through somatic hypermutation occurs in a particular B cell differentiation pathway, namely the proliferation of B cells and their maturation into memory or plasma cells in germinal centers. In this pathway the hypermutation mechanism (whose molecular basis remains to be elucidated) is turned on through an unknown (T cell-derived?) signal and is later turned off to allow the stable expression of the affinity-matured secondary antibody repertoire.

Taken together, affinity maturation of antibodies is mainly based on a process of somatic evolution in which somatic antibody mutants are generated at high rate upon T cell-dependent immunization, and high-affinity mutants selected by antigen. This allows the antibody system to rapidly adapt to any given immune stimulus - the key requirement of acquired immunity. Only in this way will the system be able to deal efficiently with microbial infection, in the course of which mutants of the infecting agent often accumulate rapidly, threatening to circumvent immune protection.

See also: Affinity; Antigen presentation via MHC class I molecules; Antigen presentation via MHC class II molecules; B lymphocyte repertoire; Clonal selection; Diversity, generation of; Germinal center; Immunoglobulin genes; Maturation of immune responses; Memory, immunological; Somatic mutation.

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