Journal Article

DZNE-2023-00775

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Low T-cell reactivity to TDP-43 peptides in ALS

Ramachandran, S. ; Grozdanov, V.Extern* ; Leins, B. ; Kandler, K. ; Witzel, S. ; Mulaw, M. ; Ludolph, A. C.DZNE* ; Weishaupt, J. H. ; Danzer, K. M. (Last author)DZNE*

2023
Frontiers Media Lausanne

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Please use a persistent id in citations: doi:10.3389/fimmu.2023.1193507

Abstract: Dysregulation of the immune system in amyotrophic lateral sclerosis (ALS) includes changes in T-cells composition and infiltration of T cells in the brain and spinal cord. Recent studies have shown that cytotoxic T cells can directly induce motor neuron death in a mouse model of ALS and that T cells from ALS patients are cytotoxic to iPSC-derived motor neurons from ALS patients. Furthermore, a clonal expansion to unknown epitope(s) was recently found in familial ALS and increased peripheral and intrathecal activation of cytotoxic CD8+ T cells in sporadic ALS.Here, we show an increased activation of peripheral T cells from patients with sporadic ALS by IL-2 treatment, suggesting an increase of antigen-experienced T cells in ALS blood. However, a putative antigen for T-cell activation in ALS has not yet been identified. Therefore, we investigated if peptides derived from TDP-43, a key protein in ALS pathogenesis, can act as epitopes for antigen-mediated activation of human T cells by ELISPOT and flow cytometry. We found that TDP-43 peptides induced only a weak MHCI or MHCII-restricted activation of both naïve and antigen-experienced T cells from healthy controls and ALS patients. Interestingly, we found less activation in T cells from ALS patients to TDP-43 and control stimuli. Furthermore, we found no change in the levels of naturally occurring auto-antibodies against full-length TDP-43 in ALS.Our data suggests a general increase in antigen-experienced T cells in ALS blood, measured by in-vitro culture with IL-2 for 14 days. Furthermore, it suggests that TDP-43 is a weak autoantigen.

Keyword(s): Humans (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; CD8-Positive T-Lymphocytes: metabolism (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; Interleukin-2 (MeSH) ; DNA-Binding Proteins ; T cells ; TDP-43 ; amyotrophic lateral sclerosis ; autoantibody ; autoantigen ; Interleukin-2 ; TARDBP protein, human

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Contributing Institute(s):

1. Mechanisms of Propagation (AG Danzer)
2. Clinical Study Center Ulm (Clinical Study Center Ulm)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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Database coverage:
; ; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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