Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy.
Alzheimer's disease is characterized by the combined presence of amyloid plaques and tau pathology, the latter being correlated with the progression of clinical symptoms. Neuroinflammatory changes are thought to be major contributors to Alzheimer's disease pathophysiology, even if their precise role still remains largely debated. Notably, to what extent immune responses contribute to cognitive impairments promoted by tau pathology remains poorly understood. To address this question, we took advantage of the THY-Tau22 mouse model that progressively develops hippocampal tau pathology paralleling cognitive deficits and reappraised the interrelationship between tau pathology and brain immune responses. In addition to conventional astroglial and microglial responses, we identified a CD8-positive T cell infiltration in the hippocampus of tau transgenic mice associated with an early chemokine response, notably involving CCL3. Interestingly, CD8-positive lymphocyte infiltration was also observed in the cortex of patients exhibiting frontemporal dementia with P301L tau mutation. To gain insights into the functional involvement of T cell infiltration in the pathophysiological development of tauopathy in THY-Tau22 mice, we chronically depleted T cells using anti-CD3 antibody. Such anti-CD3 treatment prevented hippocampal T cell infiltration in tau transgenic animals and reverted spatial memory deficits, in absence of tau pathology modulation. Altogether, these data support an instrumental role of hippocampal T cell infiltration in tau-driven pathophysiology and cognitive impairments in Alzheimer's disease and other tauopathies.
1 Univ. Lille, Inserm, CHU-Lille, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.
Cyril
C
Laurent
2 INSERM, UMRS 938, CdR Saint-Antoine, Laboratory Immune System, Neuroinflammation and Neurodegenerative Diseases, Hôpital St-Antoine, Paris, France.|3 Sorbonne Universités, UPMC Univ Paris 06, UMRS 938, CdR Saint-Antoine, Hôpital Saint-Antoine, Paris, France.
Guillaume
G
Dorothée
4 Inserm, U 1127, F-75013, Paris, France.|5 CNRS, UMR 7225, F-75013, Paris, France.|6 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.|7 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
Stéphane
S
Hunot
4 Inserm, U 1127, F-75013, Paris, France.|5 CNRS, UMR 7225, F-75013, Paris, France.|6 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.|7 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
Elodie
E
Martin
4 Inserm, U 1127, F-75013, Paris, France.|5 CNRS, UMR 7225, F-75013, Paris, France.|6 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.|7 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
Yann
Y
Monnet
2 INSERM, UMRS 938, CdR Saint-Antoine, Laboratory Immune System, Neuroinflammation and Neurodegenerative Diseases, Hôpital St-Antoine, Paris, France.|3 Sorbonne Universités, UPMC Univ Paris 06, UMRS 938, CdR Saint-Antoine, Hôpital Saint-Antoine, Paris, France.
Marie
M
Duchamp
2 INSERM, UMRS 938, CdR Saint-Antoine, Laboratory Immune System, Neuroinflammation and Neurodegenerative Diseases, Hôpital St-Antoine, Paris, France.|3 Sorbonne Universités, UPMC Univ Paris 06, UMRS 938, CdR Saint-Antoine, Hôpital Saint-Antoine, Paris, France.
Yuan
Y
Dong
4 Inserm, U 1127, F-75013, Paris, France.|5 CNRS, UMR 7225, F-75013, Paris, France.|6 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.|7 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
François-Pierre
FP
Légeron
1 Univ. Lille, Inserm, CHU-Lille, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.
Antoine
A
Leboucher
1 Univ. Lille, Inserm, CHU-Lille, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.
Sylvie
S
Burnouf
1 Univ. Lille, Inserm, CHU-Lille, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.
Emilie
E
Faivre
1 Univ. Lille, Inserm, CHU-Lille, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.
Kévin
K
Carvalho
1 Univ. Lille, Inserm, CHU-Lille, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.
Raphaëlle
R
Caillierez
1 Univ. Lille, Inserm, CHU-Lille, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.
Nadège
N
Zommer
1 Univ. Lille, Inserm, CHU-Lille, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.
Dominique
D
Demeyer
1 Univ. Lille, Inserm, CHU-Lille, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.|8 BioImaging center of Lille, 59045 Lille, France.
Nathalie
N
Jouy
4 Inserm, U 1127, F-75013, Paris, France.|5 CNRS, UMR 7225, F-75013, Paris, France.|9 Laboratoire de Neuropathologie Escourolle, Hôpital de la Salpêtrière, AP-HP, Paris, France.
Veronique
V
Sazdovitch
1 Univ. Lille, Inserm, CHU-Lille, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.
Susanna
S
Schraen-Maschke
4 Inserm, U 1127, F-75013, Paris, France.|5 CNRS, UMR 7225, F-75013, Paris, France.|6 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.|7 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
Cécile
C
Delarasse
1 Univ. Lille, Inserm, CHU-Lille, UMR-S 1172, Alzheimer and Tauopathies, Lille, France.
Luc
L
Buée
1 Univ. Lille, Inserm, CHU-Lille, UMR-S 1172, Alzheimer and Tauopathies, Lille, France david.blum@inserm.fr.
David
D
Blum
D000368:Aged; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002540:Cerebral Cortex / Q000276:immunology*; D018925:Chemokines / Q000276:immunology*; D060825:Cognitive Dysfunction / Q000276:immunology* / Q000628:therapy; D004195:Disease Models, Animal; D006624:Hippocampus / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D024801:Tauopathies / Q000276:immunology* / Q000628:therapy
D000906:Antibodies; D017252:CD3 Complex; D018925:Chemokines
T cells; chemokines; frontotemporal lobar degeneration; neuroinflammation; tauopathy