Symposia Symposien

Symposium 1: Molecular basis of the immune response

Molekulare Mechanismen der Immunantwort

Molecular basis of antigen recognition by B and T cells

Michael Steinmetz

Basel Institute for Immunology, Grenzacher Strasse 487, CH-4005 Basel, Switzerland

Molekulare Grundlage der Antigenerkennung dureh B- und T-Zellen

Three different gene families of common evolutionary ancestry code for proteins that are intimately involved in recognition of foreign antigens by the immune system have been examined. These are the immunoglobulin genes which are expressed by B cells, the T-cell receptor genes coding for the antigen receptor on T cells and the class I and class II genes of the major histocompatibility complex (MHC), coding for cell surface molecules that are corecognized with foreign antigen by the T- cell receptor (Fig. 1) (for a review see: Steinmetz lID.

Immunoglobulin molecules are usually composed of four polypeptide chains, two identical light chains and two identical heavy chains. Two different types of light chains (2 and to) and eight different classes of heavy chains (#, 6, 73, 71, y2b, 72a, e, ~) have been identified in the mouse. Each chain is composed of a variable, N-terminal portion, which shows amino acid sequence variation primarily in three hypervariable regions when chains of the same type or class are compared, and a constant C-terminal portion which shows little or no variation, The variable regions of light and heavy chains form the antigen binding site, while the constant regions are involved in effector functions carried out by the molecule after antigen binding.

Very similar to the immunoglobulin molecule, the T-cell receptor molecule, composed of two polypeptide chains (c~ and fi), contains N-terminal variable regions involved in antigen binding and C-terminal constant regions.

Cloning and characterization of the genes coding for immu- noglobulin and T-cell receptor molecules has shown that the variable regions are encoded by multiple gene segments that rearrange during B-cell and T-cell differentiation. Both gene families are using three different strategies to generate diversity in the antigen combining site: combinatorial joining of multiple gene segments, flexibility in the exact joining site used with the random insertion of nucleotides at the site of joining, and combinatorial association of distinct light and heavy chains. In addition, the immunoglobulin repertoire, but not the T-cell receptor repertoire, is expanded by a somatic hyperrnutation mechanism.

Antigen

Immunoglebulin Antigen

Tcell receptor

Fig. 1. B and T lymphocytes use two distinct ways to recognize foreign antigens. While immunoglobulin molecules, synthesized by B cells, bind soluble antigen, T cells recognize antigen on the surfaces of antigen presenting cells only in association with a class I or a class II molecule of the major histocompatibility complex (MHC)

The class I and class II cell surface molecules of the MHC are also composed of N-terminal variable and C-terminal constant regions. In contrast to the immunoglobulin and T-cell receptor molecules, however, variability is n o t generated during the lifetime of an individual by somatic rearrangement and mutational mechanisms but during evolution by three different recombinational mechanisms operating on germline DNA. In addition to the accumulation of point mutations, homologous and equal recombination preferably at recombinational hot spots, homologous but unequal recombination and gene conversion-like events contribute to the generation and mainte- nance of variability or polymorphism. It is believed that MHC polymorphism is important for a species to close holes in the T- cell repertoire that arise in given individuals due to tolerization of self determinants.

References

1. Steinmetz M (1986) Genes of the immune system. In: Rigby PWJ (ed) Genetic engineering, vol 5. Academic Press, Lon- don, in press

Fresenius Z Anal Chern (1986) 324:201 �9 Springer-Verlag 1986

201