A Critical Role for Stat3 Signaling in Immune Tolerance

Abstract

Antigen-presenting cells (APCs) can induce T cell activation as well as T cell tolerance. The molecular mechanisms by which APCs regulate this critical decision of the immune system are not well understood. Here we show that Stat3 signaling plays a critical role in the induction of antigen-specific T cell tolerance. Targeted disruption of Stat3 signaling in APCs resulted in priming of antigen-specific CD4(+) T cells in response to an otherwise tolerogenic stimulus in vivo. Furthermore, APCs devoid of Stat3 effectively break antigen-specific T cell anergy in vitro. Conversely, increased Stat3 activity in APCs led to impaired antigen-specific T cell responses. Stat3 signaling provides, therefore, a novel molecular target for manipulation of immune activation/tolerance, a central decision with profound implications in autoimmunity, transplantation, and cancer immunotherapy.

Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1)

“…Given that STAT3 can be activated by a variety of quite diverse tyrosine kinases (23), that it is persistently activated in a large spectrum of malignancies and, finally, that the STAT3 activation plays a key role in oncogenesis (24)(25)(26), it is likely that STAT3 is involved in inducing immune evasion of a substantial number of tumors. Of note, STAT3 has also been implicated in down-regulation of immune response in tumors by indirectly inhibiting activation of tumor-infiltrating antigen-presenting cells (27) and directly inducting anergy in such cells (28). However, the exact molecular mechanisms of this immunosuppression are currently unknown and the potential role of CD274, IL-10, and TGF-␤ in the process remains to be determined.…”

The Activity of JAK/STAT and NF-κB in Patients with Rheumatoid Arthritis

“…The available research results also suggest that STAT1 activates the expression of the genes coding proinflammatory proteins in some RA patients [13]. The proinflammatory nature of STAT3 in RA pathogenesis is supported by its anti-apoptotic activity profile and the stimulation of the growth of synoviocytes, T cells, and antibody synthesis [14,15]. Mori et al showed that STAT3 is the key mediator of both chronic inflammation and joint degradation in RA.…”

Tumor stress, cell death and the ensuing immune response

“…86,87 In particular, signal transducer and activator of transcription 3 (STAT3) is frequently activated in cancers and mediates immune suppression by inhibiting the expression of proinflammatory chemokines and cytokines required for DC maturation. 88 In addition, STAT3 activation in tumor cells promotes STAT3 activation in DC and blunts their functions 89 as well as the migration of immune effectors into tumor beds. Independently, tumor cells could also express PD-L1/B7-H1, B7-H4 or IDO (indolamine 2,3-dioxygenase) which induce anergy or apoptosis of tumor-specific T cells.…”