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Regulatory T cells (Tregs) exert inhibitory function under various physiological conditions and adopt diverse characteristics following environmental cues. Multiple subsets of Tregs expressing master transcription factors of helper T cells such as RORγt, T‐bet, Gata3 and PPARγ have been characterized, but the molecular mechanism governing the differentiation of these subsets remains largely unknown. Here we report that the atypical IκB protein family member Bcl‐3 suppresses RORγt+ Treg accumulation. The suppressive effect of Bcl‐3 was particularly evident in the mouse immune tolerance model of anti‐CD3 therapy. Using conditional knockout mice, we illustrate that loss of Bcl‐3 specifically in Tregs was sufficient to boost RORγt+ Treg formation and resistance of mice to dextran sulfate sodium‐induced colitis. We further demonstrate the suppressive effect of Bcl‐3 on RORγt+ Treg differentiation in vitro. Our results reveal a novel role of nuclear factor‐kappa B signaling pathways in Treg subset differentiation that may have clinical implications in immunotherapy. [ABSTRACT FROM AUTHOR]

Summary Bcl-3 is an atypical member of the IκB family that modulates transcription in the nucleus via association with p50 (NF-κB1) or p52 (NF-κB2) homodimers. Despite evidence attesting to the overall physiologic importance of Bcl-3, little is known about its cell-specific functions or mechanisms. Here we demonstrate a T-cell-intrinsic function of Bcl-3 in autoimmunity. Bcl-3-deficient T cells failed to induce disease in T cell transfer-induced colitis and experimental autoimmune encephalomyelitis. The protection against disease correlated with a decrease in Th1 cells that produced the cytokines IFN-γ and GM-CSF and an increase in Th17 cells. Although differentiation into Th1 cells was not impaired in the absence of Bcl-3, differentiated Th1 cells converted to less-pathogenic Th17-like cells, in part via mechanisms involving expression of the RORγt transcription factor. Thus, Bcl-3 constrained Th1 cell plasticity and promoted pathogenicity by blocking conversion to Th17-like cells, revealing a unique type of regulation that shapes adaptive immunity. [ABSTRACT FROM AUTHOR]

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumour cells, but not in most normal cells, and has attracted considerable attention for its potential use in cancer therapy. Recently, increasing evidence has shown that TRAIL is involved in inflammation, although much of this evidence is controversial. In this article, it is shown that TRAIL induces CXCL2, CCL4 and CCL20 secretion in a nuclear factor kappa B-dependent manner. The dominant negative constructs of tumour necrosis factor receptor-associated death domain protein (TRADD) and tumour necrosis factor receptor-associated factor 2 are unable to block TRAIL-induced chemokine up-regulation, and the dominant negative construct of TRADD may even enhance TRAIL-triggered signals. Using small interfering RNA, receptor interacting protein has been demonstrated to be essential for TRAIL-induced chemokine release. Furthermore, it has been demonstrated that p38 mitogen-activated protein kinase is involved in TRAIL-induced chemokine release without any effects on nuclear factor kappa B activation, suggesting that some unknown transcription factors may be activated by TRAIL. Using a xenograft tumour model, it has been illustrated that TRAIL can also induce chemokine release in vivo. Although these chemokines induced by TRAIL are inflammatory chemokines, their functions are not restricted to inflammation and require further examination. Our results indicate that attention should be paid to the side-effects of TRAIL treatment, not only in TRAIL-resistant but also in TRAIL-sensitive tumour cells. [ABSTRACT FROM AUTHOR]

Bcl-3 is an atypical member of the IκB family that acts in the nucleus to modulate transcription of many NF-κB targets in a highly context-dependent manner. Accordingly, complete Bcl-3-/- mice have diverse defects in both innate and adaptive immune responses; however, direct effects of Bcl-3 action in individual immune cell types have not been clearly defined. Here, we document a cell-autonomous role for Bcl-3 in CD8+ T cell differentiation during the response to lymphocytic choriomeningitis virus infection. Single-cell RNA-seq and flow cytometric analysis of virus-specific Bcl3-/- CD8+ T cells revealed that differentiation was skewed towards terminal effector cells at the expense of memory precursor effector cells (MPECs). Accordingly, Bcl3-/- CD8+ T cells exhibited reduced memory cell formation and a defective recall response. Conversely, Bcl-3-overexpression in transgenic CD8+ T cells enhanced MPEC formation but reduced effector cell differentiation. Together, our results establish Bcl-3 as an autonomous determinant of memory/terminal effector cell balance during CD8+ T cell differentiation in response to acute viral infection. Our results provide proof-of-principle for targeting Bcl-3 pharmacologically to optimize adaptive immune responses to infectious agents, cancer cells, vaccines and other stimuli that induce CD8+ T cell differentiation. Author summary: Effective immunity to previously encountered pathogens or vaccines depends on efficient formation of memory T and B cells. A major cornerstone is the generation of memory CD8+ T cells, which kill cells infected with intracellular pathogens, including viruses. In addition, memory CD8+ T cells are critical for adoptive immunotherapy to eliminate targeted tumor cells. Hence, it is essential to have a detailed understanding of pathways and molecular factors that regulate T cell differentiation/memory formation during the initial immune effector response. Here we show a critical cell-autonomous role for Bcl-3, an atypical member of the IκB family, in the regulation of CD8+ T cell differentiation/memory formation during acute viral infection with lymphocytic choriomeningitis virus. We found that Bcl-3 dampens the terminal differentiation of CD8+ T cells, which normally results in death at the end of the primary effector response, and instead, promotes the formation of memory precursor cells early on. This led to a robust memory response and much improved viral clearance upon re-challenge. Our results provide new insight into the molecular regulation of CD8+ T cell effector response and memory cell generation, establishing Bcl-3 and its pathways as a target to optimize CD8+ T cell effector responses to various immunogens including infectious agents, cancer cells, and vaccines. [ABSTRACT FROM AUTHOR]