Immune Netw.  2021 Oct;21(5):e33. 10.4110/in.2021.21.e33.

Induction of Unique STAT Heterodimers by IL-21 Provokes IL-1RI Expression on CD8 ⁺ T Cells, Resulting in Enhanced IL-1β Dependent Effector Function

• Kim DH
• Kim HY
• Lee WW

• KMID: 2522151
• DOI: http://doi.org/10.4110/in.2021.21.e33

Abstract

IL-1β plays critical roles in the priming and effector phases of immune responses such as the differentiation, commitment, and memory formation of T cells. In this context, several reports have suggested that the IL-1β signal is crucial for CTL-mediated immune responses to viral infections and tumors. However, little is known regarding whether IL-1β acts directly on CD8 ⁺ T cells and what the molecular mechanisms underlying expression of IL-1 receptors (IL-1Rs) on CD8 ⁺ T cells and features of IL-1R ⁺ CD8 ⁺ T cells are. Here, we provide evidence that the expression of IL-1R type I (IL-1RI), the functional receptor of IL-1β, is preferentially induced by IL-21 on TCR-stimulated CD8 ⁺ T cells. Further, IL-1β enhances the effector function of CD8 ⁺ T cells expressing IL-21-induced IL-1RI by increasing cytokine production and release of cytotoxic granules containing granzyme B. The IL-21-IL-1RI-IL-1β axis is involved in an augmented effector function through regulation of transcription factors BATF, Blimp-1, and IRF4. Moreover, this axis confers a unique effector function to CD8 ⁺ T cells compared to conventional type 1 cytotoxic T cells differentiated with IL-12. Chemical inhibitor and immunoprecipitation assay demonstrated that IL-21 induces a unique pattern of STAT activation with the formation of both STAT1:STAT3 and STAT3:STAT5 heterodimers, which are critical for the induction of IL-1RI on TCR-stimulated CD8 ⁺T cells. Taken together, we propose that induction of a novel subset of IL-1RI-expressing CD8 ⁺ T cells by IL-21 may be beneficial to the protective immune response against viral infections and is therefore important to consider for vaccine design.

Keyword

IL-1 Receptor; IL-1 Beta; IL-21; Cytotoxic T Lymphocyte; STAT transcription factors; Tc1 cells