Volume: 5, 2026
5th International PhD Students’ Conference at the University of Life Sciences in Lublin, Poland:
ENVIRONMENT – PLANT – ANIMAL – PRODUCT
Abstract number: H001
DOI: https://doi.org/10.24326/ICDSUPL5.H001
Published online: 22 April 2026
Beyond apoptosis: calpains as a guardian of immune quiescence and self-tolerance – a systematic review
Ashfaq Ahmad1*, Ewa Bryl2, Tamas Fulop3 and Jacek M. Witkowski1*
1 Department of Embryology, Medical University of Gdańsk, 13 Dębowa St., 80-204 Gdańsk, Poland
2 Department of Pathophysiology, Medical University of Gdańsk, 13 Dębowa St. 13, 80-204 Gdańsk, Poland
3 Research Center on Aging, Graduate Program in Immunology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC, Canada
* Corresponding author: ashfaq.ahmad@gumed.edu.pl; jacek.witkowski@gumed.edu.pl
The immune system is a paradox of precision, capable of mounting rapid, life-saving responses while simultaneously maintaining self-tolerance to prevent autoimmune destruction. At the heart of this delicate balance lie calpains, a set of calcium-dependent proteases long considered a mere executor of apoptosis. However, emerging evidence reveals a far more profound role: calpains are master regulators of immune quiescence and self-tolerance, ensuring that lymphocytes do not engage in unwarranted activation or self-reactivity. In this review, we challenge the traditional view of calpains as proapoptotic enzymes and redefine them as molecular checkpoints that govern immune homeostasis. We explore how calpain-mediated proteolysis of key immune substrates – including, but not limited to CD3ζ, ZAP-70, NF-κB, and Cyclin D1- prevents spontaneous T-cell activation, enforces metabolic restraint, and fine-tunes receptor signaling thresholds. We propose that calpains’ dysfunction is a previously overlooked driver of autoimmune diseases, where excessive proteolysis leads to immune suppression, while inadequate cleavage permits unchecked activation. We further examine the implications of calpain-targeted immunotherapies, hypothesizing that modulating calpain activity could restore immune tolerance in autoimmunity, enhance immune checkpoint function in chronic infections and cancer, and serve as a novel biomarker of immune dysregulation. Finally, we outline the open questions that define the future of this field: Can calpain inhibitors fine-tune immunity without immunosuppression? Do calpains’ cleavage determine the fate of exhausted T cells in cancer? Can calpains serve as a molecular switch or regulator for T-cell activation thresholds? By uncovering calpain’s previously hidden role as a guardian of immune quiescence, this review redefines our understanding of immune regulation and opens a new frontier in precision immunotherapy.
Keywords: calpains; immune quiescence; immune self-tolerance; T-cell activation
How to cite
Ahmad A., Bryl E., Fulop T., Witkowski J.M., 2026. Beyond apoptosis: calpains as a guardian of immune quiescence and self-tolerance – a systematic review. In: 5th International PhD Students’ Conference at the University of Life Sciences in Lublin, Poland: Environment – Plant – Animal – Product. https://doi.org/10.24326/ICDSUPL5.H001