Interleukin-2 shapes the cytotoxic T cell proteome and immune environment sensing programs

The cytokine interleukin-2 (IL-2) is critical for the differentiation and proliferation of effector CD8+ cytotoxic T cells. IL-2 signaling is mediated through the tyrosine kinases JAK1 and JAK3. Because of the importance of this pathway in orchestrating immune responses, it is an attractive target for therapies, including tofacitinib, which inhibits JAK1/3 signaling and ameliorates autoimmune and inflammatory conditions. Rollings et al. performed proteomics analysis of cytotoxic CD8+ T cells that were cultured in the presence or absence of IL-2, as well as those treated with tofacitinib, and identified proteins in IL-2–treated cells that were critical to maintain their effector function. In addition, IL-2 shaped the ability of these cells to respond to their environment by inducing the production of proteins involved in nutrient sensing and uptake, as well as in oxygen sensing. A factor involved in oxygen sensing was decreased in response to tofacitinib, giving important insights into how such drugs control immune cell function.

Interleukin-2 (IL-2) and Janus kinases (JAKs) regulate transcriptional programs and protein synthesis to promote the differentiation of effector CD8+ cytotoxic T lymphocytes (CTLs). Using high-resolution mass spectrometry, we generated an in-depth characterization of how IL-2 and JAKs configure the CTL proteome to control CTL function. We found that IL-2 signaling through JAK1 and JAK3 (JAK1/3) increased the abundance of a key subset of proteins to induce the accumulation of critical cytokines and effector molecules in T cells. Moreover, IL-2 maintained the concentration of proteins that support core metabolic processes essential for cellular fitness. One fundamental insight was the dominant role for IL-2 in stimulating effector T cells to detect microenvironmental cues. IL-2–JAK1/3 signaling pathways thus increased the abundance of nutrient transporters, nutrient sensors, and critical oxygen-sensing molecules. These data provide key insights into how IL-2 promotes T cell function and highlight signaling mechanisms and transcription factors that integrate oxygen sensing to transcriptional control of CD8+ T cell differentiation.