A Role for Epitope Networking in Immunomodulation by Helminths

E. Jane Homan, Robert D. Bremel

Helminth infections, by nematodes, trematodes, or cestodes, can lead to the modulation of host immune responses. This allows long-duration parasite infections and also impacts responses to co-infections. Surface, secreted, excreted, and shed proteins are thought to play a major role in modulation. A commonly reported feature of such immune modulation is the role of T regulatory (Treg) cells and IL-10. Efforts to identify helminth proteins, which cause immunomodulation, have identified candidates but not provided clarity as to a uniform mechanism driving modulation. In this study, we applied a bioinformatics systems approach, allowing us to analyze predicted T-cell epitopes of 17 helminth species and the responses to their surface proteins. In addition to major histocompatibility complex (MHC) binding, we analyzed amino acid motifs that would be recognized by T-cell receptors [T-cell-exposed motifs (TCEMs)]. All the helminth species examined have, within their surface proteins, peptides, which combine very common TCEMs with predicted high affinity binding to many human MHC alleles. This combination of features would result in large cognate T cell and a high probability of eliciting Treg responses. The TCEMs, which determine recognition by responding T-cell clones, are shared to a high degree between helminth species and with Plasmodium falciparum and Mycobacterium tuberculosis, both common co-infecting organisms. The implication of our observations is not only that Treg cells play a significant role in helminth-induced immune modulation but also that the epitope specificities of Treg responses are shared across species and genera of helminth. Hence, the immune response to a given helminth cannot be considered in isolation but rather forms part of an epitope ecosystem, or microenvironment, in which potentially immunosuppressive peptides in the helminth network via their common T-cell receptor recognition signals with T-cell epitopes in self proteins, microbiome, other helminths, and taxonomically unrelated pathogens. Such a systems approach provides a high-level view of the antigen-immune system signaling dynamics that may bias a host's immune response to helminth infections toward immune modulation. It may indicate how helminths have evolved to select for peptides that favor long-term parasite host coexistence.