Evolution Of Recognition Molecules: The Immunoglobulin Super Family
At this point it may be worth re-emphasizing the difference between ‘innate’ and ‘adaptive’ immunity, which lies essentially in the degree of discrimination of the respective recognition systems.
Innate immune recognition, e.g. by phagocytic cells, NK cells or the alternative complement pathway, uses a limited number of different receptors (more are being discovered all the time, but there are probably only a few dozen in total), which have evolved to recognize directly the most important classes of pathogen (see Figs 3 and 5).
Because antibody was the first of these genetic systems to be identified, they are often collectively referred to as the immunoglobulin gene superfamily, which contains other related molecules too, some with immunological functions, some without. What they all share is a structure based on a number of folded sequences about 110 amino acids long and featuring β-pleated sheets, called domains (shown in the figure as oval loops protruding from the cell membrane).
Much work is still needed to fill in the evolutionary gaps, and the figure can only give an impression of what the relationships between this remarkable family of molecules may have been. Their present-day structure and function are considered in more detail in the following four figures.
P? The precursor gene from which the immunoglobulin superfamily is presumed to have evolved. It is believed that the key to the evolutionary success of the characteristic immunoglobulin domain is its extreme resistance to chemical or physical destruction. The gene has not been identified in any existing species, but may well have coded for a molecule that mediated cell–cell recognition. Alternative mechanisms for generating very diverse families of recognition molecules have been discovered very recently in several invertebrates and primitive vertebrates, some of which seem to be based on the leucine-rich repeat (LRR) protein domain instead of the immunoglobulin domain (see Fig. 5).
V, C A vital early step seems to have been the duplication of this gene into two, one of which became the parent of all present-day variable
(V) genes and the other of constant (C) genes. In the figure, the genes and polypeptides with sufficient homology to be considered part of the V gene family are shown in blue. Subsequent further duplications, with diversification among different V and C genes, led ultimately to the large variety of present-day domains.
Major histocompatibility complex The genes shown are those found in humans, also known as HLA (human leucocyte antigen) genes. Interactions between MHC molecules and T-cell receptors are vital to all adaptive immune responses. Further details are shown in Fig. 11.
β2M β2-Microglobulin, which combines with class I chains to complete the four-domain molecule.
Gene rearrangement A process found only in T and B cells, through which an enormous degree of receptor diversity is generated by bringing together one V gene and one J gene (and one D gene in the case of IgH chains), each from a set containing from 2 to over 100. The joins between the segments are imprecise, leading to millions of possible receptors (see Figs 12 and 13). This unique process of chromosomal gene rearrangement is brought about by enzymes called recombinases.
T-cell receptor (TCR) A complex of T-cell surface molecules, including TCR α plus β, or γ plus δ chains, CD3 and CD4 or CD8, depending on the type of T cell. Together these form a unit that enables the T cell to recognize a specific antigen plus a particular MHC molecule, to become activated and to carry out its function (help, cytotoxicity, etc.; for more details see Fig. 12).
Antibody The antibody or immunoglobulin molecule plays the part of cell-surface receptor on B lymphocytes as well as being secreted in vast amounts by activated B cells to give rise to serum antibody, a vital part of defence against infectious organisms. The domains are fairly similar to those of the TCR α and β chains, but assembled in a different way, with two four-domain heavy (H) chains bonded to two two-domain light (L) chains (see Figs 13 and 14).
Note that the process of diversification in the genes for the various chains has not always proceeded in the same way. For example, mammalian heavy and light (κ) chains have all their J genes together, between V and C, while light (λ) chains have repeated J–C segments and sharks have the whole V–D–J–C segment duplicated, a considerably less efficient arrangement for generating the maximum diversity.
Costimulatory molecules T-cell proliferation and cytokine release (see Fig. 21) is governed both by the TCR binding to antigen presented on MHC molecules (see Fig. 18) and by interactions between cell molecules on the membrane of T cells and their partners (ligands) on the antigen-presenting cell. Many of these molecules belong to the immunoglobulin superfamily. Some (e.g. CD28 on the T cell and CD80 or CD86 on the antigen-presenting cell) increase the activation of the T cell (see also Fig. 12). Others, e.g. CTLA4 and PD1 on the T cell, and their ligands on the antigen-presenting cell inhibit T-cell activation, and act to limit or switch off the immune response. Several viruses seem to be able to increase expression of these negative regulators in order to escape being killed by the immune system.
Poly-Ig receptor A molecule found on some epithelial cells that helps to transport antibody into secretions such as mucus. Many other molecules contain the characteristic immunoglobulin superfamily domain structure, including some Fc receptors, adhesion molecules (see below) and receptors for growth factors and cytokines. The common feature seems to be an involvement in cell–cell interactions, with the ‘breakaway’ immunoglobulin molecule the exception rather than the rule.
Killer inhibitory receptors (KIR) Immunoglobulin-family receptors are found on NK cells (see Fig. 15). They recognize MHC molecules on target cells and send negative signals to NK cells that inhibit their activation, and hence prevent killing of targets. NK cells are therefore active only against cells that have lost MHC expression, either as a result of infection (e.g. by viruses) or as a result of malignant trans- formation (i.e. cancer cells). Some NK cells also express other negative receptors that belong to a different structural family of molecules known as C-lectins. An inhibitory signalling motif (known as an immunoreceptor tyrosine-based inhibitory motif, ITIM) on KIR cytoplasmic tails has an important role in the signal transduction process.
Adhesion molecules A large range of surface molecules help to hold cells together and facilitate cell–cell interactions or binding to blood vessel walls. Many of these are involved in regulating inflammation (see Fig. 7) and attempts to block them for therapeutic purposes are being actively explored. Some of these, as shown in the figure, belong to the immunoglobulin superfamily, and they usually bind to one or a small number of corresponding ‘ligands’. Some examples of pairs of molecules important in adhesion are shown in the table. Many of these molecules have both ‘common’ names and CD numbers (see Appendix III).