Chandelier
Senior Member (Voting Rights)
Antigen presentation by CD40+MHC-II+ astrocytes promotes CNS autoimmunity
Abstract
Astrocytes contribute to the pathology of multiple neurological disorders, including the T cell-driven autoimmune disease of the central nervous system (CNS) multiple sclerosis and its mouse model, experimental autoimmune encephalomyelitis.
However, little is known about functional interactions between astrocytes and CD4+ T cells.
Here using rabies barcode interaction detection followed by sequencing, in combination with single-cell RNA sequencing, in vitro co-culture systems and cell-specific in vivo CRISPR–Cas9-based genetic perturbation studies, we established that astrocytes expressing CD40 and MHC-II promote CNS T cell autoimmunity.
We harnessed universal labelling immune partnerships by SorTagging intercellular contacts to analyse astrocyte-interacting CD4+ T cells, finding that direct astrocyte–CD4+ T cell interactions enhance pathogenic T helper 17 cell responses in experimental autoimmune encephalomyelitis.
In addition, we studied the effect of these interactions on astrocytes. Using in vivo subproteomic approaches and AlphaFold-Multimer predictions, we established that CD40 activation in astrocytes by CD40L expressed by CD4+ T cells induces the accumulation of PLIN4-positive lipid droplets, which provide acetyl-CoA to promote p65 acetylation-dependent NF-κB activation and antigen presentation.
Finally, we detected CD40+MHC-II+LD+ astrocytes in multiple sclerosis samples by single-nucleus RNA sequencing and immunohistochemistry.
In summary, these studies define a previously unrecognized mechanism by which astrocytes promote CNS autoimmunity.
Web | DOI | PDF | Nature | Paywall
Lee, Joon-Hyuk; Li, Zhaorong; Soto, Joselyn S.; Kim, Ah-Ram; Illouz, Tomer; Polonio, Carolina M.; Kilian, Michael; Kenison, Jessica E.; Schüle, Anton M.; Akl, Camilo Faust; Lee, Hong-Gyun; Andersen, Brian M.; Ye, Jessica J.; Rone, Joseph M.; Piester, Gavin; Srun, Lena; Martinez, Jazmin; Danko, Austin; Lee, Jinsu; Heo, Tae Hyun; Chung, Elizabeth N.; Oetjen, Landon K.; Duart-Abadia, Pere; Koo, Nakyung; Perrimon, Norbert; Wheeler, Michael A.; Khakh, Baljit S.; Zandee, Stephanie E. J.; Prat, Alexandre; Quintana, Francisco J.
Abstract
Astrocytes contribute to the pathology of multiple neurological disorders, including the T cell-driven autoimmune disease of the central nervous system (CNS) multiple sclerosis and its mouse model, experimental autoimmune encephalomyelitis.
However, little is known about functional interactions between astrocytes and CD4+ T cells.
Here using rabies barcode interaction detection followed by sequencing, in combination with single-cell RNA sequencing, in vitro co-culture systems and cell-specific in vivo CRISPR–Cas9-based genetic perturbation studies, we established that astrocytes expressing CD40 and MHC-II promote CNS T cell autoimmunity.
We harnessed universal labelling immune partnerships by SorTagging intercellular contacts to analyse astrocyte-interacting CD4+ T cells, finding that direct astrocyte–CD4+ T cell interactions enhance pathogenic T helper 17 cell responses in experimental autoimmune encephalomyelitis.
In addition, we studied the effect of these interactions on astrocytes. Using in vivo subproteomic approaches and AlphaFold-Multimer predictions, we established that CD40 activation in astrocytes by CD40L expressed by CD4+ T cells induces the accumulation of PLIN4-positive lipid droplets, which provide acetyl-CoA to promote p65 acetylation-dependent NF-κB activation and antigen presentation.
Finally, we detected CD40+MHC-II+LD+ astrocytes in multiple sclerosis samples by single-nucleus RNA sequencing and immunohistochemistry.
In summary, these studies define a previously unrecognized mechanism by which astrocytes promote CNS autoimmunity.
Web | DOI | PDF | Nature | Paywall
