The anticipatory capacity of the immune system

To be able to manifest their effector functions, all lymphocytes have to bind to antigen in a specific way, namely through their antigen receptor. The question is how the immune system manages to create receptors for antigens that it, and even the organism's ancestors, might never have encountered before.

As a first approximation, this is thought to be realized by the immune system making a large, diverse set of receptors that could potentially bind anything but the self molecules. Namely, through combinatorial assembly, a relatively small number of gene fragments, give rise to a large number of immune receptors. Before the cells start circulating in the body, their receptors are "tested" for the ability to bind self, and those that bind are deleted. It is only the remaining cells that move throughout the body, constituting the naive repertoire, the repertoire prior to any exposure to antigens. By construction, whatever these receptors bind is non-self. The hope is that when a harmful microorganism (pathogen) infects the host, there will be some cells of the naive repertoire that will interact with it. This mechanism is anticipatory in the sense that no prior knowledge of the pathogens needs to go in the construction of the immune receptors that can bind these pathogens. However, at any point in time, the immune system can only circulate a limited number of lymphocytes, and thereby a limited variety of receptors, through the body. It therefore seems crucial that the immune system make optimal use of its limited resources by somehow placing its receptors "strategically" in the space of possible receptors. If antigens are more likely to have certain shapes than others, one would expect the immune system to create receptors preferentially at locations in "shape space" where antigens are most likely to occur.

 

  

Figure 1.2: Processes leading to the synthesis of the immunoglobulin heavy chain.

The sequencing of the genes encoding the immune receptors revealed an astonishing organization, never before encountered in other genes. B cell receptors are tetramers and T cell receptors are dimers, made of four and two protein chains, respectively (Fig. ). Each of these chains is the result of a combinatorial assembly process (1983) that concatenates two or three gene fragments. What makes immune receptors so special is that in the genome of each individual there are multiple genes, with somewhat different sequences, that encode one part of an immune receptor. That is, there are libraries of gene fragments (1978) (Fig. ). In the case of the light chain, these fragments are denoted by V (variable) and J (joining). The heavy chain has an extra D (diversity) fragment, inserted between its own V and J fragments. A subscript is used to denote the homonymous fragments in the heavy and the light chains. In humans, for example, there are 39-45 different functional V_H genes, 23-30 different D genes, and 6 different J_H genes. Each chain receives, at its end, a constant fragment, C, responsible for its effector function. The recombination process leading to the synthesis of the immunoglobulin heavy chain is shown in Fig. . When the V(D)J fragments are assembled into the rearranged gene, their ends may be trimmed, and an enzyme, terminal deoxynucleotidyl transferase (TdT), adds at the junction nucleotides that were not encoded in the genome (1993). Finally, during an immune response, B cells that have been selected for interaction with the pathogen undergo mutation of the rearranged immunoglobulin gene (1970). Within a special environment, the germinal centers of the lymphoid organs, this process of somatic hypermutation is coupled to selection for efficient interaction with the pathogen, and leads to what is called affinity maturation. The memory population of B cells coming out of the germinal centers has a higher average affinity of immune receptors and is generally more efficient in clearing the pathogen at subsequent encounters. Yet another diversity-generating mechanism operates on rearranged V(D)J genes in species such as chicken and rabbit. Chickens have only one functional V gene. Rabbits have more than one, but one of these genes is responsible for 80% of the rearrangements. After the whole receptor gene has been assembled through rearrangement, another, yet uncharacterized, mechanism replaces part of the gene with a copy of a gene fragment coming from another V gene or pseudogene in the genome. This process is called gene conversion (Fig. ).

 

Thus, there are multiple sources of diversity in B cell receptors:

• Whereas most other proteins in the body are encoded by one gene, or multiple identical copies of a gene, each of the gene fragments that is used in assembling immune receptor genes has multiple, non-identical variants in the genome. Each B cell in turn uses exclusively one member of this set for its receptor.
• Each of the B cell receptor chains is randomly assembled from 2 (the light chain) or 3 (the heavy chain) gene fragments. Once this rearrangement occurs, the B cell generally does not undergo subsequent rearrangements.
• During the rearrangement process, the ends of the gene fragments undergo processing, some of the nucleotides being lost, and others, for which no genetic information was present, may be added.
• During the germinal center reaction, individual B cells may accumulate mutations in the gene encoding their immune receptor. These mutations only affect individual B cells, and are not recorded in the gene libraries that the organism transmits to its offspring. Whereas the organization of the immunoglobulin gene libraries and their rearrangement mechanism evolve on the level of the whole organism, the germinal center reaction constitutes an evolutionary process on the level of individual B cells.

Due to molecular biology techniques, we now know what mechanisms are responsible for creating diverse immune receptors. Diversity, however, cannot be the goal. After all, assembling an immune receptor in a non-template manner, just like TdT does with the junctional regions, would be a better way to create diverse receptors. The genes encoding immune receptors are carrying some information, and what that information might be is the question that stirred my interest.