Mehdi Jorfi 1,2,3,5, Joseph Park1,2,5, Clare K. Hall1, Chih-Chung Jerry Lin1, Meng Chen1, Djuna von Maydell1, Jane M. Kruskop1, Byunghoon Kang1, Younjung Choi1, Dmitry Prokopenko1,2, Daniel Irimia 2,3,4, Doo Yeon Kim 1,2 & Rudolph E. Tanzi 1,2
1Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
2Harvard Medical School, Boston, MA, USA.
3Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Charlestown, MA, USA.
4Shriners Burns Hospital, Boston, MA, USA.
5These authors contributed equally: Mehdi Jorfi, Joseph Park.
Corresponding authors : Correspondence to Mehdi Jorfi, Doo Yeon Kim or Rudolph E. Tanzi.
Brain infiltration of peripheral immune cells and their interactions with brain-resident cells may contribute to Alzheimer’s disease (AD) pathology. To examine these interactions, in the present study we developed a three-dimensional human neuroimmune axis model comprising stem cell-derived neurons, astrocytes and microglia, together with peripheral immune cells. We observed an increase in the number of T cells (but not B cells) and monocytes selectively infiltrating into AD relative to control cultures. Infiltration of CD8+ T cells into AD cultures led to increased microglial activation, neuroinflammation and neurodegeneration. Using single-cell RNA-sequencing, we identified that infiltration of T cells into AD cultures led to induction of interferon-γ and neuroinflammatory pathways in glial cells. We found key roles for the C-X-C motif chemokine ligand 10 (CXCL10) and its receptor, CXCR3, in regulating T cell infiltration and neuronal damage in AD cultures. This human neuroimmune axis model is a useful tool to study the effects of peripheral immune cells in brain disease.