Research Program

The Brutkiewicz Laboratory investigates how innate immune pathways contribute to neurological disease and seeks to identify novel immunological targets for therapeutic intervention. Our work is grounded in a long-standing interest in antigen presentation and unconventional T cell biology, with a current emphasis on neuroinflammation, Alzheimer's disease (AD), traumatic brain injury (TBI), and post-traumatic epilepsy.

Research Vision

The central premise of our research is that immune responses that normally protect the host can become maladaptive in the central nervous system, driving chronic inflammation and neurodegeneration. We aim to define the cellular and molecular mechanisms that connect antigen presentation pathways, innate-like T cells, glial activation, and neuronal dysfunction.

By integrating immunology, neuroscience, and translational disease models, we seek to identify immune pathways that can be therapeutically targeted to slow or prevent neurological disease progression.

Major Research Areas

MR1 and MAIT Cells in Alzheimer's Disease

Our laboratory has established that the major histocompatibility complex class I-related molecule MR1 and mucosal-associated invariant T (MAIT) cells contribute to Alzheimer's disease pathology. We demonstrated that disruption of the MR1/MAIT cell axis slows amyloid-β pathology and alters neuroinflammatory responses in mouse models of AD. We are currently investigating:

·        How MAIT cells become activated during disease

·        The cellular sources and identity of MR1-presented ligands in the brain

·        Interactions between MAIT cells, microglia, astrocytes, and brain endothelial cells

·        The contribution of peripheral immune organs, particularly the liver, to disease progression

·        Therapeutic targeting of the MR1/MAIT pathway in Alzheimer's disease

Our long-term goal is to determine whether this immune axis represents a druggable pathway for neurodegenerative disorders.

Neuroinflammation and Glial Cell Biology

We study how astrocytes and microglia detect pathological signals and propagate inflammatory responses in the CNS. Current projects focus on:

·         Mechanisms of microglial activation in Alzheimer's disease

·         Astrocyte-mediated inflammatory signaling

·         Antigen presentation within the CNS

·         Crosstalk between innate and adaptive immune cells during neurodegeneration

These studies seek to define how resident brain cells shape disease progression and influence neuronal survival.

Immune Mechanisms of Traumatic Brain Injury and Epilepsy

Another area of investigation is the role of innate-like T cells in post-traumatic epilepsy. Using experimental models of TBI, we have shown that the CD1d/NKT cell axis plays a critical role in the development of cortical hyperexcitability and seizure susceptibility.

Current efforts seek to:

·         Define immune mechanisms underlying epileptogenesis

·         Identify neuroimmune biomarkers of disease progression

·         Evaluate immune-targeted therapeutic strategies following brain injury

·         Determine how antigen presentation pathways regulate neuroinflammation after trauma

These studies may provide a foundation for the development of preventive therapies for post-traumatic epilepsy.

Antigen Presentation and Unconventional T Cell Biology

Our laboratory has a long-standing interest in mechanisms regulating antigen presentation by CD1d and MR1 molecules and how these pathways influence innate immune responses.

Ongoing studies examine:

·         Regulation of MR1 antigen presentation

·         Cellular signaling pathways controlling unconventional antigen presentation

·         Activation and function of MAIT and invariant NKT cells

·         Immune evasion strategies used by pathogens and diseased tissues

These investigations provide fundamental insights into how innate-like T cells influence human disease.

Experimental Approaches

The laboratory employs a multidisciplinary approach that integrates:

·         Transgenic and disease-model mice

·         Flow cytometry and high-parameter immune profiling

·         Single-cell transcriptomic analyses

·         Human brain tissue studies

·         Advanced imaging and microscopy

·         Molecular and cellular immunology

·         Neurobehavioral and neuropathological assessments

This combination of approaches enables mechanistic investigation from molecular pathways to whole-animal disease outcomes.