Cross-reactivity of B and T cells: desired in influenza vaccine responses, feared in autoimmune diseases

Abstract

Innate immune mechanisms are very efficient at mounting rapid immune responses at the site of infection. Complete clearance of a pathogen and long-lasting protection through memory formation requires the adaptive immune system. To be able to cope with the large variety of pathogens we encounter, T and B cells acquire an almost infinite number of specificities by VDJ-recombination and somatic hypermutation. However, not all recombinations are equally likely to occur and the majority of lymphocyte clones will never be released from the thymus or bone marrow due to negative selection. T cells also need to recognize host HLA-proteins, adding further constraints. Therefore, immune cell diversity is more restricted than theoretically possible. A certain redundancy is induced by the fact that a T or B cell clone may recognize multiple epitopes, albeit with different affinities, a feature termed cross-reactivity. In a vaccine against a genetically diverse pathogen, cross-reactivity of vaccine-induced immune cells is desirable. An ideal vaccine enables the host to mount an immune response not only against the vaccine strain but also against naturally occurring variants that may be antigenically different. Influenza virus is one of the most prevalent human pathogens and of high economic relevance. The ‘success’ of influenza virus is tightly linked to its extraordinary ability to evolve – that is, evading the host’s immune system – while still maintaining its integrity and virulence. Annually updated influenza vaccines provide some protection against infection. However, vaccine efficacy is strongly reduced when there is an antigenic mismatch between vaccine strain and predominant circulating virus. We hypothesized that the cross-reactivity of the influenza vaccine response is affected by the individual B cell repertoire and wanted to test whether low cross-reactivity associates with a narrow repertoire. A narrow antibody repertoire could be related to the previous infection history or to repetitive vaccination with very similar influenza vaccine strains. Consequently, this may lead to higher susceptibility to emerging viral variants. The breadth and degree of antigen-specificity of the B cell receptor (BCR) repertoire can be assessed by sequencing the immunoglobulin heavy chains before and after vaccination. We tested this hypothesis by analyzing samples from a previous cohort of influenza-vaccinated healthy subjects and aimed to extend our findings by conducting a prospective clinical influenza vaccination study in individuals with known vaccination history. Since the composition of the influenza vaccine is an active debate in the field, our results could inform on both strain selection and better vaccination strategies. Cross-reactivity can be beneficial in the case of vaccination but may be harmful if cross-reactive lymphocytes target self-structures, as it is the case in autoimmunity. While B cells recognize native macromolecular structures, T cells mainly respond towards peptides displayed on MHC of antigen-presenting cells (APC). In Giant Cell Arteritis (GCA), a disease affecting medium-sized and large arteries, considerable infiltration of CD4+ T cells is found in the affected vessels. Several lines of evidence suggest that these T cells are not just merely attracted to a site of inflammation, but rather might recognize a specific antigen. Whether this is a primary response against a microbial or self-protein or infection-induced cross-reactivity to self-proteins is currently unknown. In order to investigate antigen involvement in GCA pathogenesis, we used an antigen-centered approach to screen for T cell reactivity against self- and candidate viral antigens. Complementary, we used a T cell receptor (TCR)-based approach in order to investigate expanded clones and enriched CDR3-motifs in the affected arteries. Finally, taking advantage of our prospective GCA cohort study at the University Hospital Basel, we tested the antibody reactivity in newly diagnosed GCA patients against a self-protein proposed by others to be important in GCA pathogenesis. These results will help us to better understand the (early) disease pathogenesis and to find possible druggable pathways.