T helper (Th) cells play a central role in orchestrating immune responses to diverse microbial pathogens [1
]. Upon activation by antigens, naive CD4+
T cells differentiate into specialized effector T (Teff) cells (Th1, Th2, or Th17), which secrete different patterns of cytokines and perform different functions [1
]. Th1 cells produce interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) and initiate cellular immune responses against intracellular pathogens. Th2 cells generate interleukin-4 (IL-4), IL-5 and IL-13 and promote humoral responses against extracellular parasites. Th17 cells make IL-17, IL-21 and IL-22 and confer immunity against extracellular bacteria and fungi. Moreover, activated CD4+
T cells also differentiate into regulatory T (Treg) cells, which express transforming growth factor-β (TGF-β), IL-10 and IL-35 and suppress the functions of Teff cells, thereby keeping immune responses in check.
Imbalance of Th cell differentiation and subsequent cytokine dysregulation is implicated in inflammatory and autoimmune diseases [2
]. In particular, Th1 and Th17 cells and their signature cytokines IFN-γ and IL-17 have been shown to play a critical role in the development of autoimmune responses in many autoimmune diseases, including multiple sclerosis (MS) and rheumatoid arthritis [2
]. In accordance with the significance of Th cell differentiation in animal physiology and pathology, the molecular mechanisms underlying this important process have been extensively investigated. In this regard, the signal transducers and activators of transcription (STAT) proteins are well known for their essential roles in transmitting cytokine-mediated signals and specifying Th cell differentiation [1
]. In general, STAT4 is activated mainly by IL-12 and type I IFNs, and it functions predominantly in promoting Th1 cell differentiation. STAT6 is activated in response to IL-4 and functions as the molecular switch for initiation of the Th2 cell differentiation program. Soon after activation by IL-6, STAT3 triggers Th17 commitment. On the other hand, IL-2-activated STAT5 facilitates Treg cell differentiation. Similar to STAT proteins, the NF-κB transcription factors, particularly the prototypical member RelA (also known as p65), are also master regulators/activators of immune responses and inflammation in both healthy and disease [5
]. The signaling pathways leading to activation of STAT and NF-κB proteins have been well demonstrated [7
]. However, it still remains largely unknown how activated STAT and NF-κB are terminated for proper Th cell differentiation and immune responses and how STAT and NF-κB are deregulated in autoimmune diseases.
Previous studies show that PDLIM2, a ubiquitously expressed PDZ-LIM domain-containing protein with high expression in lymphoid tissues and cells including T lymphocytes, is required for the termination of STAT and NF-κB activation [9
]. More recent studies suggest that PDLIM2 may function as a tumor suppressor [11
]. Mechanistic studies indicate that PDLIM2 selectively promotes ubiquitination and proteasomal degradation of nuclear (activated) STAT4 and RelA proteins [9
]. However, whether and how PDLIM2 is involved in Th cell differentiation remain unknown. In particular, mouse genetic studies reveal that PDLIM2 is not required for the development of immune cells and immune tissues/organs [9
]. Additionally, it remains unknown whether PDLIM2 is involved in the pathogenesis of inflammatory and autoimmune diseases.