Brian Baker

Research Interests

Research in the Baker lab is directed at the biochemical and biophysical underpinnings of molecular recognition, emphasizing cellular immunity and its role in infection and disease, autoimmunity, cancer, and transplantation. We are primarily interested in antigen presentation by major histocompatibility complex molecules, their recognition by T cell receptors, and the design and engineering of novel therapeutics based on T cell-mediated immunity. Our approach integrates structural biology, protein biophysics, computational biochemistry, molecular immunology, and a growing amount of machine learning and artificial intelligence.

Most cells in the body express class I or class II major histocompatibility complex proteins, or MHC proteins, which bind and “present” peptides derived from intracellular or extracellular proteins. Recognition of a peptide/MHC complex by a T cell receptor (TCR) on the surface of a helper or cytotoxic T cell stimulates a T cell-mediated immune response. While best recognized for its role in the immune response to viruses, T cell mediated immunity also plays a key role in the immune response to other pathogens, in cancer, autoimmunity, and transplant rejection.

Many projects in the lab are centered on the structural, biophysical, and immunological principles of TCR recognition of peptide/MHC complexes. The TCR-pMHC interaction is one of the most complex protein-ligand interactions known to biology. We aim to understand the complexities from a physical perspective, relying heavily on structural biology and experimental and computational biochemistry, but also an increasing amount of data science and in vitro and in vivo immunology. Our overall aims are to understand how TCR recognition influences immunity in health and disease.

As we gain insight into TCR recognition of peptide/MHC, we are using this knowledge to engineer TCRs with improved recognition properties with the goal of developing novel therapeutics. Other projects are centered on understanding how recognition is communicated across the cell membrane. Here, we aim to gain a deeper understanding of the physical changes that occur upon binding and how these influence protein architecture, motion, and connections with cell signaling units. The influence of applied forces on protein complexes in the immune system is a new and exciting area of emphasis.

We have a special interest in the immune response to cancer. There is a close connection between cellular immunity and cancer, and in a very short time, immunotherapy has emerged as a fourth “pillar” of cancer therapy. We study the development of exciting, new personalized vaccines for cancer as well as sophisticated approaches that involve the creation of genetically engineered immune systems for cancer patients. In these areas, we leverage our understanding of the structural and biophysical underpinnings of TCR recognition of peptide/MHC to help drive advances in cancer immunology. A new focus on the lab is the T cell immunology of transplant rejection, and how we can leverage our understanding to better predict, monitor, and control outcomes in transplantation.

Our lab is highly collaborative, and we work with a range of chemists, biologists, and clinicians, including academic and industry teams engaged in a variety of clinical trials, ranging from cancer vaccines, to the latest cell therapies, to novel means to control the rejection of transplanted organs.

Selected Publications

• Kobeissi, H.; Jilberto, J.; Karakan, M. C.; Gao, X.; DePalma, S. J.; Das, S. L.; Quach, L.; Urquia, J.; Baker, B. M.;Chen, C. S.; Nordsletten, D.; and Lejeune, E. "MicroBundleCompute: Automated Segmentation, Tracking, and Analysis of Subdomain Deformation in Cardiac Microbundles" 2024 PLoS One, 19 (3), e0298863. DOI: 10.1371/journal.pone.0298863.
• Rosenberg, A. M.; Ayres, C. M.; Medina-Cucurella, A. V.; Whitehead, T. A. and Baker, B. M. "Enhanced T Cell Receptor Specificity through Framework Engineering" 2024 Frontiers in Immunology, 15, 1345368. DOI: 10.3389/fimmu.2024.1345368.
• Antunes, D. A.; Baker, B. M.; Cornberg, M. and Selin, L. K. "Quantification and Prediction of T-Cell Cross-Reactivity through Experimental and Computational Methods" 2024 Frontiers in Immunology, 15, 1377259. DOI: 10.3389/fimmu.2024.1377259.
• Mikhaylov, V.; Brambley, C. A.; Keller, G.; Arbuiso, A. G.; Weiss, L. I.; Baker, B. M. and Levine, A. J. "Accurate Modeling of Peptide-MHC Structures with AlphaFold" 2024 Structure, 32 (2), pp. 228-241. DOI: 10.1016/j.str.2023.11.011.
• Custodio, J. M.; Ayres, C. M.; Rosales, T. J.; Brambley, C. A.; Arbuiso, A. G.; Landau, L. M.; Keller, G.; Srivastava, P. K. and Baker, B. M. "Structural and Physical Features that Distinguish Tumor- Controlling from Inactive Cancer Neoepitopes" 2023 Proceedings of the National Academy of Sciences of the United States of America, 120 (51), e2312057120. DOI: 10.1073/pnas.2312057120.
• Khorki, M. E.; Shi, T.; Cianciolo, E. E.; Burg, A. R.; Chukwuma, P. C.; Picarsic, J. L.; Morrice, M. K.; Woodle, E. S.; Maltzman, J. S.; Ferguson, A.; Katz, J. D.; Baker, B. M. and Hildeman, D. A. "Prior Viral Infection Primes Cross-Reactive CD8+T Cells that Respond to Mouse Heart Allografts" 2023 Frontiers in Immunology, 14, 1287546. DOI: 10.3389/fimmu.2023.1287546.

>> See our full list of publications at PubMed >>