Interleukin 33: a switch-hitting cytokine

Abstract

For many years IL-33 has been widely studied in the context of T helper type 2 (Th2)-driven inflammatory disorders. Interestingly, IL-33 has now emerged as a cytokine with a plethora of pleiotropic properties. Depending on the immune cells targeted by IL-33, it is reported to not only promote Th2 immunity, but also to induce T helper type 1 (Th1) immunity. Furthermore, recent studies have revealed that IL-33 can activate CD8(+) T cells. These new studies provide evidence for its beneficial role in antiviral and antitumor immunity. Here we review the evidence of IL-33 to drive protective T cell immunity plus its potential use as an adjuvant in vaccination and tumor therapy.

Figure 1

Immunoadjuvant properties of administered full-length IL-33 (proIL-33) and/or mature IL-33 (mtrIL-33) on tumor and viral growth. These observed effects are determined by the specific cells targeted and the associated cytokine network. Administration of either proIL-33 or mtrIL-33 has been described as having cellular activities on NK/NKT, CD4⁺, and effector CD8⁺ T cells which produce Th1-associated protective immunity. Concomitantly, M1 macrophages and APCs produce and secrete IL-12, which then induces expression of ST2 on NK/NKT cells and CD8⁺ T cells, permitting IL-33 to induce Th1-associated cytokine production. It is unclear whether Th1 CD4⁺ T cells are able to upregulate ST2, however, IFNγ production by other activated immune cells likely leads to their amplification which then can help activate antiviral and tumoricidal immunity. Interestingly, recent evidence hints at a new activity for proIL-33 as it has been found to elicit antigen-specific antibodies, yet its role in protection against infectious pathogens remains to be determined. Notes: APC, antigen-presenting cells; NK, natural killer cells; NKT, natural killer T cells; Teff, effector memory CD8 T cells; Tcm, central memory CD8 T cells