The adaptive immune response selectively expands B and T-cell clones following antigen recognition by the B- or T-cell receptors (BCR and TCR) respectively. Currently the diversification and dynamics of adaptive immune responses during infection, malignancy and autoimmunity remain poorly understood.
To address this, we present a novel method of sampling human B and T-cell populations at high-resolution, using next-generation sequencing of BCRs and TCRs coupled with novel repertoire analyses. These methods allow us to dissect the different components of the adaptive immune response and enable detection of lymphocyte clones in chronic lymphocytic leukemia (CLL) to exquisite sensitivity.
We show BCR sequences organise into networks based on sequence diversity, which clearly distinguish between the diverse repertoires of healthy individuals and clonally expanded repertoires from individuals with CLL. Network connectivity measures of BCR diversity provide a proxy to the B-cell clonality status of individuals with decreasing network Rényi entropy strongly correlating with the time from CLL diagnosis. We correlated the repertoire diversity of the heavy and light immunoglobulin chains with TCR diversities to better understand the relationships between these immune subsets.
Associations between BCR network entropy and disease stage or other clinical parameters offer a novel diagnostic & prognostic dimension for clonal blood disorders. This approach can also be used to enhance our understanding of the dynamics of the immune response in infectious disease and to help deconvolute host-pathogen interactions. These studies provide important insights into the evolution of both dominant and rare clonal species of B and T-cell populations, and the dynamic and complex adaptive immune responses.
Supported by the Wellcome Trust.