Question

Do every MHC class II molecule on a single dendritic cell present the same peptide fragment?

Answer 1

The answer is no.

MHC Class 2 molecules on a particular DC can present different peptides to CD4 T cells.

MHC I and MHC II molecules are unique in the proteome because of their extreme polymorphism (>10,000 different alleles of MHC I molecules have been identified thus far!). This has interesting consequences. Polymorphic residues on the top alpha helixes interact with the TCR and are the basis for the specificity of TCRs for both an antigen peptide plus a particular allelic form of an MHC molecule (a phenomenon called MHC restriction). Polymorphic residues in the MHC peptide binding groove change the nature and location of so-called pockets. These variable pockets are filled by complementary variable amino acid side chains of peptides (so-called anchor residues), with the effect that different fragments from a defined antigen are presented by different polymorphic MHC molecules. Yet, next to the anchor residues, most other amino acids in a peptide fill a free space and can be (almost) any of the 20 amino acids. By having pockets with specificity for only a few side chains and allowing the remaining 6–10 amino acids to vary between all possibilities, each kind of MHC molecules can present a very large repertoire of peptides. Moreover, by having 3 to 6 different MHC I as well as 3 to 12 different MHC II molecules (the exact number depending on how many different MHC alleles were inherited from one’s parents and how the MHC II subunits paired), cells can present a large fraction of the universe of peptides, although not all sequences. In theory then, MHC I molecules can present a peptidome of around 6 × 20(6–7) different peptides, and MHC II can display up to 12 × 20(10) peptides. In actuality, such a large array of peptides cannot all be presented because there are only around 200,000 MHC I and 20,000 MHC II molecules on cells such as B and T cells. Moreover, since some peptides are present in high number (from highly expressed proteins), the real number of different peptides presented by one cell is likely less than 10,000. Importantly, when a pathogen alters a critical anchor residue in one of its antigenic epitopes, it may prevent presentation of this antigen in one individual but not in another person with different MHC molecules that will simply select different peptides from the same pathogen.Therefore, MHC polymorphism is good for the survival of the population and not necessarily the individual.

Please refer to the following papers for further reading and reference:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839614/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159193/