Figure 24–39 The processing of an extracellular protein antigen for presentation to a helper T cell. This simplified depiction shows how peptide–class-II-Mhc complexes are formed in endosomes and delivered via vesicles to the cell surface. Viral envelope glycoproteins can also be processed by this pathway for presentation to helper T cells (not shown): these glycoproteins are normally made in the er and transported via the Golgi for insertion into the plasma membrane; although most of these glycoproteins will be incorporated into the envelope of budding viral particles, some will be endocytosed and enter endosomes, from where they can enter the class II Mhc processing pathway. RECOGNITION BY HELPER T CELL DELIVERY OF PEPTIDE– MHC COMPLEX TO PLASMA MEMBRANE FOR RECOGNITION BY HELPER T CELL Golgi apparatus trans Golgi class II MHC protein late endosome early endosome folded protein antigenplasma membrane DENDRITIC OR TARGET CELL LIMITED PROTEOLYSIS OF ANTIGEN AND INVARIANT CHAIN LEAVES FRAGMENT OF INVARIANT CHAIN IN BINDING GROOVE OF MHC PROTEIN RELEASE OF INVARIANT CHAIN FRAGMENT AND BINDING OF ANTIGEN-DERIVED PEPTIDE INVARIANT CHAIN DIRECTS CLASS II MHC PROTEIN TO LATE ENDOSOME ENDOCYTOSIS AND DELIVERY TO ENDOSOME fragment of invariant chain CYTOSOL antigenic peptide
During an infection, only a small fraction of the many thousands of MHC proteins on the surface of an APC or target cell will have pathogen peptides bound to them. This is sufficient, however: fewer than 50 copies of such a peptide–MHC complex on a dendritic cell, for example, can activate a helper T cell that has a TCR that binds the complex with a high-enough affinity. Table 24–3 compares the properties of class I and class II MHC proteins.
Mhc proteins Are the Most polymorphic human proteins Known
Although any individual can make only a small number of different class I and class II MHC proteins, together, these proteins must be able to present peptide fragments from almost any foreign protein to T cells. Thus, unlike the antigen-binding site of an Ig protein, the peptide-binding groove of each MHC protein must be able to bind a very large number of different peptides. The genes encoding class I and class II MHC proteins (see Figure 24–37) are the most polymorphic known in higher vertebrates: in the human population, for example, there are more than 2000 allelic variants of these genes. The corresponding variations in the MHC proteins are concentrated in the floor and walls of the peptide-binding grooves and allow MHC molecules in different individuals to bind different arrays of peptides.
It is thought that infectious diseases have been an important driving force for generating this remarkable MHC polymorphism. In the evolutionary war between pathogens and the adaptive immune system, pathogens will tend to change their proteins through mutation so that the peptides derived from them will not fit in the MHC peptide-binding grooves. When a pathogen succeeds, it can sweep through a population as an epidemic. In such circumstances, the few individuals who produce a new allelic form of MHC protein that can bind peptides derived from the altered pathogen will have a large selective advantage. This type of selection will tend to promote and maintain a large diversity of MHC proteins in the population. In West Africa, for example, individuals with a specific MHC allele (HLA-B53) have a reduced susceptibility to a severe form of malaria that is endemic there; although this allele is rare elsewhere, it is found in 25% of the West African population.