"Altered cytokine signaling in STAT3 gain-of-function dysregulates CD8+ T cell function"

Jose S. Campos, Peyton Conrey, Samir Sayed, Chao Di, Jennifer Leiding, Lisa Forbes Satter, Steven Holland, Alexandra Freeman, Tiphanie Vogel and Sarah E. Henrickson

T cell exhaustion (Tex) develops in the setting of chronic antigen exposure and inflammation (e.g., cancer and chronic viral infection) and is characterized by altered transcriptional circuitry and epigenetic states, co-expression of immunoregulatory receptors, impaired effector function, and mitochondrial dysfunction. The role of T cell receptor (TCR) signaling in Tex has been well established, but little is known about how non-TCR signals, such as cytokine signaling pathways, may initiate, maintain, or augment Tex. However, emerging evidence suggests that chronic inflammation alone may be sufficient to yield Tex. Here, we focus on inborn errors of immunity patients with signal transducer and activator of transcription 3 gain-of-function (STAT3GOF) mutations. Specifically, these patients have genetically amplified inflammatory cytokine signaling which can be used to study the possible relationship between chronic inflammation and Tex. To assess how STAT3GOF mutations impact immune cell subset distribution, we performed high dimensional immune profiling via mass cytometry on PBMCs from STAT3GOF patients and age-matched controls. This revealed altered states of CD8+ T cell activation with increased expression of immunoregulatory receptors (e.g., PD-1 and CD39) which correlates with the amplitude of STAT3 signal. Functional testing showed impaired cytokine production and reduced proliferative capacity relative to age-matched healthy controls. Sorted CD8+ T cells from STAT3GOF patients show an exhausted-like transcriptional profile. In vitro, healthy donor CD8+ T cells persistently exposed to STAT3-activating cytokines (e.g., IL-6) show impaired function. Thus, gain-of-function mutations in STAT3 provide a unique model to study the effect of upregulated cell signaling pathways on immune function ex vivo. An improved understanding of how altered STAT3 signaling patterns affect T cell function may help identify mechanisms of dysregulation that can be targeted therapeutically in these patients as well as others who share dysregulated STAT3 signaling (e.g., obesity) and have increased frequency of T cell dysfunction.