This conversation was led by Tobias L. Lenz of the Research Group for Evolutionary Immunogenomics at the Max Planck Institute for Evolutionary Biology in Ploen, Germany. Pathogen-mediated selection is a major driver of human evolution in general and of immune gene diversity specifically. A key component of the adaptive immune system are the human leukocyte antigen (HLA) genes, coding for molecules that present antigenic peptides to immune effector cells. The exceptional polymorphism at the HLA gene is assumed to reflect the need for diverse antigen presentation. However, an optimal immune response requires a delicate balance of maximizing recognition of pathogens while minimizing damage to self tissue by the immune machinery. As HLA molecules present both non-self and self antigens, depending on which antigens are presented by an individual’s HLA variants, this can trigger either pathogen resistance or autoimmunity. HLA-presentation of a broader antigen repertoire should thus be beneficial for pathogen recognition, but might also increase the risk for autoimmunity, leading to antagonistic selective pressures that shape the optimal antigen repertoire and thus HLA diversity in an individual.
Here Dr. Lenz discussed this evolutionary trade-off for individual HLA diversity and present some examples from his work on the role of pathogens in the evolution of HLA diversity, but also on its consequences for autoimmunity and its role in immune checkpoint blockade therapy against cancer, a striking example for the success of evolutionary medicine.
- Pierini and Lenz 2018, “Divergent allele advantage at human MHC genes: signatures of past and ongoing selection“
- Chowell et al. 2019, “Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy“