NK cell presentation- Sim Group
- Sim Group
In the Sim lab we study peptide-specific immune receptors. We’re interested in understanding the molecular basis for how these receptors achieve peptide specificity and exploiting this property for immunotherapy. We use molecular, cellular and structural techniques with most lab members gaining experience in flow cytometry based functional immunology experiments and protein production/engineering.
The archetypal peptide-specific receptor is the T cell receptor (TCR), which detects peptide antigens presented on class I and class II major histocompatibility complex molecules (MHC-I & MHC-II). T cells can eliminate cancer by detecting neoantigen peptides presented on MHC molecules. We study how TCRs detect ‘public’ neoantigens, those derived from common cancer mutations such as those in p53, KRAS and EGFR. Current projects investigate the molecular basis for T cell detection of these neoantigens and engineering these TCRs for enhanced sensitivity and therapeutic efficacy.
MHC-I and MHC-II molecules also serve as ligands for numerous immune receptors, many of which do not interact with the bound peptide directly. However, some germline-encoded receptors, typically expressed on natural killer (NK) cells can interact with MHC-I in a highly peptide specific manner. These receptors include members of the killer-cell immunoglobulin-like receptor (KIR) family. Previous work demonstrated that some KIR display exquisite peptide-specificity, reminiscent of TCRs, however the immunological purpose of the specificity is not clear. A major focus of the lab is to understand the role of these peptide specific NK cell receptors by investigating two main areas. First, we are developing high throughput approaches to define the peptide-specificity of KIR in unprecedented detail. We will use these data to build computational models that can predict KIR binding peptides from immunopeptidomes and cancer genomes to uncover the role of KIR-mediated peptide-specificity in response to cancer. In the second approach, we’re developing in vitro systems to investigate how NK cells integrate signals from peptide-specific receptors such as KIR with the multitude of activating and inhibitory receptors expressed by NK cells. We will determine the cellular context in which peptide-specific NK cell receptors are most likely to determine target cell fate with focus on understanding the sensitivity of these receptors to antigen dose and co-stimulation. Our goal is to leverage these insights into targeting NK cells in cancer immunotherapy and to develop a broader understanding for the role of KIR in human immunology.
Our team
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Malcolm Sim
MRC Career Development Fellow, Junior Group leader
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Beining Li
Research Assistant
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Tanusya Murali
Postdoctoral Scientist
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Emery Hoos
DPhil student (NIH-Oxford)
