Limited T-cell presence despite extensive microglial HLA class II expression in the frontal cortex in Alzheimer’s disease

Abstract Background: Upregulation of HLA class II in amyloid plaque-associated microglia is one of the most prominent immune-associated features of the Alzheimer’s disease (AD) brain in large-scale human brain single nuclei RNA-sequencing and spatial transcriptomic data sets. This HLA class II response is part of a broader programme that includes co-stimulatory and co-inhibitory molecules involved in T-cell regulation. T-cell signatures are however sparse in these datasets. Methods: We therefore investigated whether the extensive upregulation of microglial HLA class II is accompanied by substantial T cell accumulation in a brain region with established AD pathology using immunohistology on postmortem brain tissue. We quantified CD3-, CD4- and CD8-positive T cells together with HLA-DR/DP/DQ-positive cells in the frontal cortex of symptomatic AD cases with confirmed local Aβ- and pTau-pathology, and in non-demented controls. Group differences in cell densities were assessed using binary logistic regression controlled for age and sex; regression analyses incorporating post-mortem interval were considered exploratory. Results: A striking numerical discrepancy between abundant HLA-DR/DP/DQ-positive microglia (on average 18 000 cells/cm 2 ) and very few parenchymal T cells (on average 8 cells/cm 2 ) in the AD frontal cortex is observed. We did not detect a significant increase in parenchymal T-cell numbers in AD compared with control cases which contrasted sharply with the dense T cell infiltrates observed in the positive-control ADEM case of acute disseminated encephalomyelitis. Conclusions: The central implication of our findings is that HLA class II expression in AD microglia should not automatically be equated with extensive T cell engagement in the brain parenchyma. It will require further molecular and spatial characterization to determine whether the rare parenchymal T cells that are present in AD, target specific antigens and have functional effects on the progression of AD. Further work is needed to discriminate the specific role of T-cells in AD versus other neurodegenerative disorders.