TY  - JOUR
AU  - Ramachandran, Swetha
AU  - Grozdanov, Veselin
AU  - Leins, Bianca
AU  - Kandler, Katharina
AU  - Witzel, Simon
AU  - Mulaw, Medhanie
AU  - Ludolph, Albert C.
AU  - Weishaupt, Jochen H.
AU  - Danzer, Karin M.
TI  - Low T-cell reactivity to TDP-43 peptides in ALS
JO  - Frontiers in immunology
VL  - 14
SN  - 1664-3224
CY  - Lausanne
PB  - Frontiers Media
M1  - DZNE-2023-00775
SP  - 1193507
PY  - 2023
AB  - 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.
KW  - Humans
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - CD8-Positive T-Lymphocytes: metabolism
KW  - DNA-Binding Proteins: metabolism
KW  - Interleukin-2
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - T cells (Other)
KW  - TDP-43 (Other)
KW  - amyotrophic lateral sclerosis (Other)
KW  - autoantibody (Other)
KW  - autoantigen (Other)
KW  - Interleukin-2 (NLM Chemicals)
KW  - TARDBP protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10401033
C6  - pmid:37545536
DO  - DOI:10.3389/fimmu.2023.1193507
UR  - https://pub.dzne.de/record/259703
ER  -