Interleukin-33 (IL-33)

Transcription factor 7 (T-cell specific, HMG-box) (TCF7) expressing CD8+ Cytotoxic T Lymphocytes (CTLs) can self-renew like stem cells, a key for immune defense against chronic viral infections and cancer. A decisive factor for this property is interleukin-33 (IL-33).
Marx et al. 2023 Immunity 56: 813–828

Interleukin-33 (IL-33), part of the Interleukin-1 (IL-1) / Interleukin-1 family, is crucial for driving protective CD8+ T cell responses against various RNA and DNA-Viruses. Released from fibroblastic reticular cells in the spleen and lymph nodes during infection, IL-33 signals through the ST2 receptor on activated CD8+ T cells, promoting their expansion and differentiation during acute viral infections. This IL-33-ST2 axis can enhance therapeutic tumor vaccination efficacy and be utilized in DNA vaccines.

Schmitz et al. 2005 Immunity 23: 479-490
Yang et al. 2011 Eur J Immunol 41: 3351-3360
Bonilla et al. 2012 Science 335: 984-989
Peine et al. 2016 Trends Immunol 37: 321-333
Kallert et al. 2017 Nat Commun 8: 15327
Aparicio-Domingo et al. 2021 Eur J Immunol 51: 76-90
Ring et al. 2021 Nat Commun 12: 4734
Li et al. 2022 Viral Immunol 35: 41-49

IL-33 is vital for CD4 and CD8 T cell differentiation during acute viral infections. It helps T cells grow and supports their functions and memory.
Bonilla et al. 2012 Science 335: 984-989
Baumann et al. 2015 Proc Natl Acad Sci USA 112: 4056-4061
Marx et al. 2023 Immunity 56: 813–828

Recent studies show IL-33 boosts CD8 T cell stemness. It enhances T cell responses in chronic infections by increasing TCF1 expression. The signaling occurs through the ST2 receptor on antiviral CD8+ T cells, significantly enhancing their capacity for re-expansion. This enhancement is linked to a broadly increased chromatin accessibility.
McLaren et al. 2019 J Immunol 202: 943-955
Marx et al. 2023 Immunity 56: 813–828

Furthermore, IL-33 signaling effectively counteracts the effects of type I interferons (IFN-I), thereby sustaining the stemness of CD8+ SL cells during chronic viral infections.
Marx et al. 2023 Immunity 56: 813–828

This early role complicates studying IL-33 in later infection stages, including tissue-resident memory T (Trm) cells.
Tovar et al. 2024 J Immunol 213(12): 1884-1892

IL-33 triggered calcium influx via a non-canonical signaling pathway specifically in Enterochromaffin Cells (EC) to induce Serotonin (5-HT) secretion. IL-33-mediated Serotonin (5-HT) release activated enteric neurons. IL-33 induced instantaneous peristaltic movement and facilitated Trichuris muris expulsion
Chen et al. 2021 Immunity 54: 151-163

Interleukin-33 (IL-33) is a multifaceted cytokine released rapidly by injury, stress and infection, which subsequently initiates an amplification of immune responses
Liew et al. 2016 Nat. Rev. Immunol. 16: 676-689
Dinarello 2018 Immunol Rev 281: 8-27

However, a physiological function of endogenous Interleukin-33 (IL-33) remains to be clarified.
Nu et al. 2022 J Immunol 208: 660-671

Interleukin-33 (IL-33) – a cytokine able to prime microglia and monocyte-derived macrophages toward phagocytic activity
Castellanii & Schwartz 2020 Trends in immunology 41: 794

The glia-derived alarmin Interleukin-33 (IL-33) plays a crucial role in coordinating the immune response and aids in recovery after central nervous system (CNS) injury
Gadani et al. 2015 Neuron 85: 703-709

see also:
Enterochromaffin Cells (EC) & Serotonin (5-HT)