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.

For additional information, please visit the Baker lab website at bmblab.nd.edu.

Selected Publications

• Eldaly, B. and Baker, B. M. "Dynamic Allostery in T Cell Receptor Specificity: A Role for Peptides and MHC Polymorphisms in Allosterically Tuning Immune Recognition" 2026 Bioessays, 48 (3), e70126. DOI: 10.1002/bies.70126.
• Adams, A. C.; Macy, A. M.; Borden, E. S.; Herrmann, L. M.; Brambley, C. A.; Sonar, S. A.; Ma, T.; Li, X.; Hughes, A.; Roe, D. J.; Mangold, A. R.; Nikolich, J. Z.; Buetow, K. H.; Wilson, M. A.; Baker, B. M. and Hastings, K. T. "Structural Changes from Wild-Type Define Tumor-Rejecting Neoantigens" 2025 Journal for Immunotherapy of Cancer, 13 (10), e013148. DOI: 10.1136/jitc-2025-013148.
• George, M. M.; Brennick, C. A.; Hagymasi, A. T.; Shcheglova, T.; Al Seesi, S.; Rosales, T. J.; Baker, B. M.; Mandoiu, I. I. and Srivastava, P. K. "A Frameshift-Generated Cancer Neoepitope that Controls Tumor Burden in Prophylaxis as Well as Therapy" 2025 Journal of Immunology, 214 (6), pp.1123–1132. DOI: 10.1093/jimmun/vkaf016.
• Ma, J. Q.; Ayres, C. M.; Brambley, C. A.; Chandran, S. S.; Rosales, T. J.; Perera, W.; Eldaly, B.; Murray, W. T.; Corcelli, S. A.; Kovrigin, E. L.; Klebanoff, C. A. and Baker, B. M. "Dynamic Allostery in the Peptide/MHC Complex Enables TCR Neoantigen Selectivity" 2025 Nature Communications, 16 (1), 849. DOI: 10.1038/s41467-025-56004-8.
• Afzal, A.; Khawar, M. B.; Gong, W. J.; Baker, B. M. and Sun, H. B. "Editorial: Specific Targeting of MHC Antigens for T-Cells and Immune Cells in Human Disease" 2025 Frontiers in Immunology, 15, 1540449. DOI: 10.3389/fimmu.2024.1540449.
• Brambley, C. A. and Baker, B. M. "Immune Tolerance in Peripheral CD4+ T Cells is Cooperatively Regulated by PD-1 and CD73" 2025 Nature Immunology, 26 (1), pp.9–10. DOI: 10.1038/s41590-024-02039-w.