Ayano Kohlbruber
Antigen-Specific Basis of Autoimmunity and Cancer
The Kohlgruber lab investigates the antigen-specific basis of human diseases and applies high-throughput molecular, genetic, and immunological assays to decipher immune system specificities and interactions. We combine primary human patient samples with mouse models of disease and use single-cell transcriptomics, synthetic biology, and T cell antigen discovery screening approaches to understand the molecular underpinnings of autoimmunity and cancer. Our overarching hypothesis is that by determining the antigens recognized by T cells during disease, we can 1) deconstruct pathological etiologies, 2) gain insight into fundamental principles of T cell homeostasis and antigen recognition, and 3) identify therapeutic targets to improve cellular therapies or vaccines that harbor curative potential for patients. Current projects in the lab focus on:
Goal 1. Determining how T cell antigens dictate autoimmune disease progression. Although we know a great deal about the phenotype and function of T cells found in blood circulation and at sites of inflammation during autoimmunity, we know very little about the antigens that mediate their activation. Even more limiting is our knowledge about the timing of when pathologic T cells arise. To gain molecular and temporal understanding, we study rheumatoid arthritis as a model disease for autoimmunity and investigate the role of T cell antigensearly during thymic selection to characterize and understand central tolerance; prior to establishment of fulminant disease where environmental triggers such as pathogenic infections may lead to generation of antigens that break T cell tolerance; and during disease where rapid and comprehensive characterization of patient T cell profiles are warranted.
Goal 2. Discovering therapeutically actionable T cell targets in cancer. Our current understanding of tumor-infiltrating T cell specificities is limited, where only a fraction of the total TCR reactivities have been captured and of those, the specificities have largely focused on CD8 T cells. In addition, immune checkpoint blockade-induced autoimmunity is common in cancer patients receiving treatment, but little is known about the antigens that drive adverse responses against self. In the lab, we assess the antigens recognized by T cells in a range of cancer types and treatments to identify what targets can form protective anti-tumor immune responses or conversely, drive pathology in patients.
Goal 3. Interrogating unconventional T cell reactivities. More than 140 unique amino acid variations can contribute to the overall composition of proteins. This dramatically increases the landscape of potential peptides that can serve as antigens for T cells. In addition, our immune system harbors conserved T cell subsets that have evolved to recognize antigens beyond our amino acid code including ligands such as lipids, phosphoantigens, and metabolites. Autoimmunity and cancer are associated with the presence of dysregulated biological pathways that result in altered modification of proteins or presentation of ligands that stimulate unconventional T cells. We are interested in developing new technologies and performing functional genomic screens to survey the T cell specificities of modified- or non-peptide antigens.
Our work lies at the intersection of translational immunology and biotechnology, where we seek to pioneer innovative strategies to improve our ability to interrogate and modulate the immune system. Our lab’s goal is to define new paradigms for comprehensively assessing T cell reactivities against diverse antigen types and contexts and deepen our understanding of the immune system during homeostasis and disease.