Supraphysiological Levels of IL-2 in Jak3-Deficient Mice Promote Strong Proliferative Responses of Adoptively Transferred Naive CD8+ T Cells.

Gil-Woo Lee,Jae-Ho Cho,Cheol-Heui Yun,Sung-Woo Lee,Hee-Ok Kim,Juhee Kim,Young-Jun Ju

doi:10.3389/fimmu.2020.616898

Abstract

The antigen-independent, strong proliferative responses of naive CD8+ T cells have been well demonstrated in a particular strain of mice lacking IL-2 receptors. This type of proliferation is mainly driven by common gamma-chain (γc) cytokines, such as IL-2, IL-7, and IL-15, present at abnormally high levels in these mice. Similarly, in the present study, we showed that mice lacking Janus kinase 3 (Jak3), a tyrosine kinase crucial for γc cytokine signaling, could induce strong proliferation of adoptively transferred naive CD8+ T cells. This proliferation was also independent of antigenic stimulation, but heavily dependent on IL-2, as evidenced by the failure of proliferation of adoptively transferred IL-2 receptor alpha- and beta-chain-deficient naive CD8+ T cells. Consistent with this, Jak3 –/– mice showed elevated serum levels of IL-2 compared to wild-type mice, and interestingly, IL-2 production was due to high levels of accumulation of activated CD4+ T cells in Jak3 –/– mice along with defective CD4+ T regulatory cells. Collectively, these findings reveal previously unidentified unique immune contexts of Jak3 –/– mice that cause robust IL-2-driven T cell expansion and have a clinical implication for designing a treatment strategy for human patients with loss-of-function genetic mutations of Jak3.

Highlights

Janus kinase 3 (Jak3) is a member of the Janus family of protein tyrosine kinases and is associated with a cytoplasmic domain of the common receptor gamma-chain shared by cytokines such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 [1, 2]
Given the functional association of Jak3 for mediating the signal transduction of gc cytokines, it has been previously demonstrated that mice lacking Jak3 have a defect in T cell development, especially the CD8+ T cell population, due to IL-7 signaling failure [9, 10, 17]
These data suggest that the tempo and type of proliferation of T cells observed in Jak3–/– mice are distinctly different from the typically slow rate of lymphopenia-induced homeostatic proliferation (LIP) [22]

Summary

Introduction

Janus kinase 3 (Jak3) is a member of the Janus family of protein tyrosine kinases and is associated with a cytoplasmic domain of the common receptor gamma-chain (gc) shared by cytokines such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 [1, 2]. IL-2-Driven T Cell Expansion in Jak3-Deficient Mice through the phosphorylation of signal transducer and activator of transcription (STAT) proteins to induce the expression of various genes and subsequent biological functions [3,4,5] Based on these roles of gc cytokines, Jak3-deficient mice have several abnormalities similar to those observed in mice lacking gc cytokines and their corresponding receptors [6,7,8]. The T cells restored in Jak3-deficient mice have been shown to display an activated T cell phenotype, such as high and low levels of CD44 and CD62L, respectively [9] These large numbers of activated T cells are likely to be associated with a defect in Treg-mediated immunosuppression in Jak3-deficient mice [12, 18], whether these cells contribute to shaping altered immune contexts in these mice remains to be addressed

Methods

Results

Conclusion