Fernandes Group | Immune signalling in health & disease
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Founded in September 2020
• Dissecting and manipulating immune receptor signalling • Discovery-led approaches to guide the engineering of novel proteins that potentiate robust immune responses against tumours and infection • Developing methods to identify targets of immune recognition
Dr Ricardo Fernandes is a Group Leader at the CAMS Oxford Institute at the University of Oxford. Ricardo obtained his PhD at Oxford, working with Simon Davis on the mechanism of TCR triggering. Later he moved to Stanford for his postdoctoral studies, where he developed novel bispecific proteins that take advantage of endogenous membrane phosphatases to shut down signalling by surface receptors. The Fernandes' Lab applies protein engineering to decipher functional and structural correlates of immune receptor signalling and identify new therapeutic approaches to modulate T cell function in autoimmune, infection and cancer settings.
The adaptive immune system effectively eliminates infected or tumour cells while sparing healthy ones by utilizing the immense molecular diversity and sensitivity of T cell receptors (TCRs). To mount an effective response, T cells incorporate signals from various surface receptors, including co-receptors such as CD28 and cytokine receptors. All these signals can promote and sustain T-cell responses. However, sustained T cell responses also lead to the expression of inhibitory receptors (IRs) that suppress T cells. Our research investigates these critical stages of the T cell response: antigen recognition by TCRs, signal integration and IR-mediated suppression of T cell effector functions.
Our group focuses on identifying and manipulating key functional aspects affecting immune responses in health and disease. To achieve this, we continuously develop new tools and strategies using various techniques, including protein engineering, protein biochemistry, directed evolution, and bioinformatics. This approach aims to:
1) Identify antigens recognized by T cells involved in anti-tumour responses;
2) Discover fundamental properties of signalling by receptors such as CD28, PD-1 and CTLA-4;
3) Engineer new proteins to manipulate T-cell responses in health and disease
We have recently developed new protein molecules to regulate the activity of inhibitory surface receptors to enhance T-cell function, named Receptor Inhibition by Phosphatase Recruitment. RIPR molecules are bispecific soluble ligands that recruit abundant phosphatases, such as CD45, to target receptors. This approach directly induces receptor dephosphorylation, thus terminating IR signalling, and remains effective regardless of ligand presence.
In addition to this, we use yeast display libraries to determine the specificity and cross-reactivity for TCRs of interest involved in detecting antigens in cancer cells. Identifying what the immune system is "seeing" is challenging due to the extreme diversity of the TCR. Using unbiased screens with millions of distinct peptides allows us to 1) determine TCR specificity and 2) de-risk engineered TCRs. We also use directed evolution to engineer modified ligands that affect signal integration.
Identifying potent peptide agonists and engineering novel protein molecules to effectively enhance anti-tumour responses by T cells provide an exciting opportunity to modulate the immune response in health and disease and interrogate fundamental aspects of T cell biology.
These efforts ultimately aim to guide the development of novel therapeutic strategies.