Brutkiewicz Lab

group photo of six people with matching shirts standing in front of a decorative wall The research lab of Randy R. Brutkiewicz, PhD, was established in 1998, and is focused on understanding the innate-like T cell populations, invariant natural killer T (iNKT) and mucosal-associated invariant T (MAIT) cells, and the MHC class I-like molecules they recognize — CD1d and MR1, respectively — in various disease states. CD1d presents lipid molecules to iNKT cells; MR1 presents microbial vitamin B metabolites to MAIT cells.

The initial contributions by the lab were focused on how virus infections altered the CD1d/NKT cell axis. It was discovered that a virus infection in vivo induced the loss of iNKT cells by apoptosis. However, viral clearance was independent of CD1d. Subsequent studies demonstrated that cytopathic viruses could disrupt the intracellular trafficking of CD1d and subsequent recognition by iNKT cells. We also identified the specific residues in the human CD1d cytoplasmic tail necessary for cell surface expression and impacted by an HSV-1 infection and HIV Nef protein.

Other work was focused on the regulation of the CD1d/NKT and MR1/MAIT cell axes via cell signaling pathways. Both p38 and JNK MAPK reduced — and ERK and PKCδ promoted — antigen presentation by CD1d. This was extended to studies showing that rho kinase, which is important in the formation of the actin cytoskeleton, was a negative regulator of CD1d-mediated antigen presentation. Moreover, it was found that the Bacillus anthracis lethal toxin inhibited antigen presentation by CD1d via the inhibition of ERK, demonstrating one mechanism of immune evasion by this pathogen.

In terms of the MR1/MAIT cell axis, it was found that E. coli activated the TLR9 signaling pathway, increasing MR1 cell surface expression and recognition by MAIT cells. This activity also required TRAF3 and IFR7, downstream participants following TLR9 activation.

Studies on the role of the CD1d/NKT cell axis in antitumor immunity demonstrated that one mechanism by which certain hematopoietic tumors can evade NKT cell recognition is by their shedding of lipids, which bind to CD1d and block their ability to present self-antigens to NKT cells. iNKT cells are well known antitumor effector cells; in the absence of iNKT cells, it was found that B cell lymphomas grow more rapidly than those animals bearing iNKT cells.

Active Research

Alzheimer’s disease (AD) is a devastating disorder for both the patients and their caregivers, with no effective cures on the near-term horizon. We have reported that the MR1/MAIT cell axis controls the temporal development of AD pathology. AD model mice lacking MR1 and MAIT cells develop amyloid beta plaques at a significantly slower rate than in those that do. Additionally, these mice have fewer dystrophic neurites and learn significantly better than their MR1+ counterparts. Moreover, brain-resident MAIT cells in MR1+ AD mice are increased in number and are in an enhanced activation state compared to normal wildtype (i.e., non-AD) mice of the same age. Looking at brain sections from actual AD patients, we found that the expression of MR1 is higher on microglia that are closer to amyloid beta plaques, as compared to those further away. This observation was also seen in brain sections from MR1+ AD mice.

The microbiome has been shown to be important in AD pathology. Considering that MR1 presents microbial antigens to MAIT cells, we asked whether the gut microbiota of MR1-deficient AD mice was different from MR1+ AD mice. MR1+ AD mice are in a higher inflammatory state than their MR1-deficient counterparts, and they have distinct differences in their gut microbiomes that reflect those differences. Moreover, we have found an association between the bacteria present in the gut microbiomes of these MR1+ and MR1-deficient AD mice, and defects in memory/learning.

Additional current studies ongoing in the laboratory are focused on better understanding the importance of MR1 expression on cells of the CNS, if there are differences in the brain cytokine milieu between MR1+ and MR1-deficient AD mice, as well as studies of the MR1/MAIT cell axis in AD patients themselves. Our overall focus for these current studies is on determining the suitability of targeting the MR1/MAIT cell axis as a novel treatment paradigm for AD patients.

In collaboration with Xiaoming Jin, it was found that both CD1d and NKT cells are required for the development of post-traumatic brain injury epilepsy. Interestingly, in a spinal cord injury model begun in collaboration with the late Xiao-Ming Xu, although the presence of CD1d delayed functional recovery, this occurred independently of NKT cells.

Research Funding and Publications

1R01 AG092565-01A1: “MR1/MAIT cell axis-mediated regulation of inflammatory responses”. 02/15/2026 – 01/31/2031. Total Costs: $3,040,446. Principal Investigator: Randy R. Brutkiewicz

R01NS125020: “Characterization of Whole Brain Demyelination and Axon Damage Using High-Resolution Magnetic Resonance Imaging”. 06/01/2022-05/31/2027. Total Costs: $1,981,250. Principal Investigator: Nian Wang. Co-Investigator: Randy R. Brutkiewicz

Falk Medical Research Trust: “Advancing traumatic brain injury therapy through targeting CD1d-lipid signaling pathways”. 11/30/2024 – 11/30/2026. Total Costs: $349,685. Principal Investigators (MPI): Randy R. Brutkiewicz, Andy Yu, Xiang Gao

Wyatt-Johnson, S.K, Kersey, H.N., Codocedo, J.F., Newell, K.L., Landreth, G.E., Lamb, B.T., Oblak, A.L. Brutkiewicz, R.R. Control of the temporal development of Alzheimer’s disease pathology by the MR1/MAIT cell axis. J. Neuroinflammation 20:78, 2023. PMID: 36944969.
Shrinivasan, R., Wyatt-Johnson, S.K., Brutkiewicz, R.R. The MR1/MAIT cell axis in CNS diseases. Brain, Behavior, and Immunity 116:321-328, 2024. PMCID: PMC10842441.
Wyatt-Johnson, S.K., Afify, R., Brutkiewicz, R.R. The immune system in neurological diseases: What innate-like T cells have to say. J. Allergy Clin. Immunol. 153(4):913-923, 2024. PMCID: PMC10999338.
Afify, R., Lipsius, K., Wyatt-Johnson, S.K., Brutkiewicz, R.R. Myeloid Antigen-Presenting Cells in Neurodegenerative Diseases: A focus on Classical and Non-Classical MHC Molecules. Front. Neurosci. (Section Neurodegeneration), 18:1488382, 2024. PMCID: PMC11667120.
Wyatt-Johnson, S.K, Kersey, H.N., Brutkiewicz, R.R. Enrichment of liver MAIT cells in a mouse model of Alzheimer’s disease. J. Neuroimmunology 390:578332, 2024. PMID: 38537322.
Wyatt-Johnson, S.K., Ackley, S., Warren, J., Raj Priya, Wan, J., Liu, S., Brutkiewicz, R.R. The MR1/MAIT cell axis enhances dystrophic neurite development in Alzheimer’s disease. Alzheimer’s Dement 21(2):e14480, 2025. PMID: 39777865. PMCID: PMC11848147.
Ping, X., Xiong, W., Priya, Raj, Liu, J., Wyatt-Johnson, S.K.; Brutkiewicz, R.R., Jin, X. Blocking the innate immune CD1d/NKT cell axis prevents the development of cortical hyperexcitability and posttraumatic epilepsy. Epilepsia 66(6):2110-2123, 2025. PMCID: PMC12169402.
Brutkiewicz, R.R., Cao, W., Morgan, D., Souza Dos Reis, R., Suryadevara, V., Willette, A.A., Willette, S.A., Wyatt-Johnson, S.K., Duggan, M.R. What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? Trends in Neurosciences 16:S0166-2236(25)00104-3, 2025.
Wyatt-Johnson, S.K., Desai, J.M., Wireman, A., Eipers, P., Morrow, C., Vornhagen, J., Brutkiewicz, R.R. The MR1/MAIT cell axis impacts the gut-brain axis through both cognition and microbial community structure in 5XFAD mice. Alzheimer’s Dement 21(7):e70493, 2025. PMID: 40696831. PMCID: PMC12284323.
Chen, J., Han, X., Liu, Z., Zhou, C.Q., Hu, R., Tabassam, S., Wyatt-Johnson, S.K., Oblak, A.L., Brutkiewicz, R.R., Lin, M., Wang, N. Detecting Beta-Amyloid Plaque via Low Rank Based Orthogonal Projection and Spatial-spectrum Detector Using High-resolution Quantitative Susceptibility Mapping for Preclinical Studies. IEEE Transactions on Biomedical Engineering PP:10.1109/TBME.2025.3614233, 2025. PMID: 40991598.