Exploring the role of T cells in Alzheimer's and other neurodegenerative diseases: Emerging therapeutic insights from the T Cells in the Brain symposium

Abstract

This proceedings article summarizes the inaugural "T Cells in the Brain" symposium held at Columbia University. Experts gathered to explore the role of T cells in neurodegenerative diseases. Key topics included characterization of antigen-specific immune responses, T cell receptor (TCR) repertoire, microbial etiology in Alzheimer's disease (AD), and microglia-T cell crosstalk, with a focus on how T cells affect neuroinflammation and AD biomarkers like amyloid beta and tau. The symposium also examined immunotherapies for AD, including the Valacyclovir Treatment of Alzheimer's Disease (VALAD) trial, and two clinical trials leveraging regulatory T cell approaches for multiple sclerosis and amyotrophic lateral sclerosis therapy. Additionally, single-cell RNA/TCR sequencing of T cells and other immune cells provided insights into immune dynamics in neurodegenerative diseases. This article highlights key findings from the symposium and outlines future research directions to further understand the role of T cells in neurodegeneration, offering innovative therapeutic approaches for AD and other neurodegenerative diseases. HIGHLIGHTS: Researchers gathered to discuss approaches to study T cells in brain disorders. New technologies allow high-throughput screening of antigen-specific T cells. Microbial infections can precede several serious and chronic neurological diseases. Central and peripheral T cell responses shape neurological disease pathology. Immunotherapy can induce regulatory T cell responses in neuroinflammatory disorders.

Keywords: Alzheimer's disease; Parkinson's disease; T cell receptor repertoire; T cells; amyotrophic lateral sclerosis; brain; central nervous system; clinical trials; conference proceedings; epilepsy; immunotherapy; major histocompatibility complex peptidome; single‐cell RNA sequencing; spinal cord; viral infection.

FIGURE 1

Schematic illustration of research topics presented at the T Cells in the Brain 2024 symposium, highlighting the discovery of antigens presented on MHC class I and II molecules in the context of neurodegenerative diseases, and the identification of clonally expanded T cells, their phenotypes, and antigen specificity using single‐cell RNA/TCR sequencing (scRNA/TCR‐seq) and TetTCR‐seqHD. Studies cover two antigen types: (1) self‐antigens potentially derived from aggregated proteins, such as amyloid beta and tau in AD, alpha‐synuclein in PD, and TDP‐43 in ALS; and (2) non–self‐antigens, including microbial antigens such as herpesviruses (e.g., HSV‐1, associated with AD) and bacteria (e.g., Porphyromonas gingivalis, also linked to AD). These antigens are processed by brain‐resident cells expressing MHC molecules: microglia, which express both MHC class I and II, and neurons, which predominantly express MHC class I. Antigen presentation leads to the recruitment of peripheral T cells to the brain border and parenchyma, where they undergo clonal expansion and activation. The cascade is modulated by genetic variants, particularly within the MHC locus, which impact immune surveillance and antigen processing. Finally, therapeutic approaches targeting T cells are discussed, including the use of regulatory T cells (Tregs) and nasal administration of anti‐CD3 monoclonal antibody (foralumab) to promote immune tolerance and potentially modulate neuroinflammation in neurodegenerative diseases. AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; CAR, chimeric antigen receptor; HSV‐1, herpes simplex virus 1; LC‐MS, liquid chromatography mass spectrometry; MHC, major histocompatibility complex; PD, Parkinson's disease; TCR, T cell receptor; TDP‐43, TAR DNA‐binding protein 43.

FIGURE 2

Schematic diagram of topics discussed at the T Cells in the Brain 2024 symposium. HLA genetic variants linked to neurodegenerative diseases, such as AD, PD, and ALS, modulate MHC molecules that play key roles in antigen presentation. These MHC molecules present disease‐associated self‐antigens (e.g., Aβ and tau in AD, α‐synuclein in PD, and TDP‐43 in ALS) as well as non–self‐antigens, including microbial antigens from herpesviruses and other microbes, leading to T cell recruitment to the CNS and clonal expansion of disease‐specific T cell phenotypes. Aging, a major risk factor for neurodegenerative diseases, exacerbates immune dysfunction and immunosenescence, further influencing T cell behavior in the CNS. To characterize T cell antigen specificity and phenotypes in these diseases, advanced techniques are used, including single‐cell RNA sequencing (scRNA‐seq) and T cell receptor sequencing (TCR‐seq) for immune profiling, MHC peptidomics to identify CNS antigens, and tetramerized TCR sequencing (TetTCR‐seq) to assess T cell reactivity. Clinical trials are underway to inhibit detrimental T cell responses, using strategies such as autologous and allogeneic Tregs, TCR‐engineered Tregs (TCR‐Tregs), CAR‐Tregs, anti‐CD3 monoclonal antibodies, and low‐dose IL‐2 to restore immune homeostasis. Specifically targeting microbial infections, Columbia University researchers are evaluating the efficacy of valacyclovir in the Valacyclovir Treatment of Alzheimer's Disease (VALAD) trial, a randomized, double‐blind, placebo‐controlled study, to assess whether antiviral treatment can mitigate neuroinflammation and slow disease progression. Aβ, amyloid beta; AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; CNS, central nervous system; HLA, human leukocyte antigen; MHC, major histocompatibility complex; PD, Parkinson's disease; TDP‐43, TAR DNA‐binding protein 43.