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| Item Type: | Article |
|---|---|
| Title: | Autoantigen-specific CD4(+) T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases |
| Creators Name: | Saggau, C., Bacher, P., Esser, D., Rasa, M., Meise, S., Mohr, N., Kohlstedt, N., Hutloff, A., Schacht, S.S., Dargvainiene, J., Martini, G.R., Stürner, K.H., Schröder, I., Markewitz, R., Hartl, J., Hastermann, M., Duchow, A., Schindler, P., Becker, M., Bautista, C., Gottfreund, J., Walter, J., Polansky, J.K., Yang, M., Naghavian, R., Wendorff, M., Schuster, E.M., Dahl, A., Petzold, A., Reinhardt, S., Franke, A., Wieczorek, M., Henschel, L., Berger, D., Heine, G., Holtsche, M., Häußler, V., Peters, C., Schmidt, E., Fillatreau, S., Busch, D.H., Wandinger, K.P., Schober, K., Martin, R., Paul, F., Leypoldt, F. and Scheffold, A. |
| Abstract: | Pro-inflammatory autoantigen-specific CD4(+) T helper (auto-Th) cells are central orchestrators of autoimmune diseases (AIDs). We aimed to characterize these cells in human AIDs with defined autoantigens by combining human leukocyte antigen (HLA)-tetramer-based and activation-based multidimensional ex vivo analyses. In aquaporin4-antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) patients, auto-Th cells expressed CD154, but proliferative capacity and pro-inflammatory cytokines were strongly reduced. Instead, exhaustion-associated co-inhibitory receptors were expressed together with FOXP3, the canonical regulatory T cell (Treg) transcription factor. Auto-Th cells responded in vitro to checkpoint inhibition and provided potent B cell help. Cells with the same exhaustion-like (ThEx) phenotype were identified in soluble liver antigen (SLA)-antibody-autoimmune hepatitis and BP180-antibody-positive bullous pemphigoid, AIDs of the liver and skin, respectively. While originally described in cancer and chronic infection, our data point to T cell exhaustion as a common mechanism of adaptation to chronic (self-)stimulation across AID types and link exhausted CD4(+) T cells to humoral autoimmune responses, with implications for therapeutic targeting. |
| Keywords: | CD4 T Cell Exhaustion, Autoantigen-Specific T Cells, Antigen-Reactive T Cell Enrichment, ARTE, Autoimmune Disease, Neuromyelitis Optica, Autoimmune Hepatitis, Bullous Pemphigoid, MOGAD, CD154, Foxp3 |
| Source: | Immunity |
| ISSN: | 1074-7613 |
| Publisher: | Cell Press / Elsevier |
| Volume: | 57 |
| Number: | 10 |
| Page Range: | 2416-2432.e8 |
| Date: | 8 October 2024 |
| Official Publication: | https://doi.org/10.1016/j.immuni.2024.08.005 |
| PubMed: | View item in PubMed |
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