NLRC5: back to innate immunity.

NLRC5 is a transcriptional regulator of genes governing T cell responses. Most characterized NLRs are instead innate immune sensors forming complexes leading to pyroptosis. Raising exciting questions, Sundaram and colleagues now demonstrate that NLRC5 forms large complexes and causes PANoptosis (immunogenic cell death), in response to heme in inflammatory contexts.

A Ménage à trois: NLRC5, immunity, and metabolism.

The nucleotide-binding and oligomerization domain-like receptors (NLRs) NLR family CARD domain-containing protein 5 (NLRC5) and Class II Major Histocompatibility Complex Transactivator (CIITA) are transcriptional regulators of major histocompatibility complex (MHC) class I and class II genes, respectively. MHC molecules are central players in our immune system, allowing the detection of hazardous 'non-self' antigens and, thus, the recognition and elimination of infected or transformed cells from the organism. Recently, CIITA and NLRC5 have emerged as regulators of selected genes of the butyrophilin () family that interestingly are located in the extended MHC locus.

Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn's Disease.

Objective: Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn's disease (CD) pathogenesis. However, the specific cell types and pathways affected as well as their potential impact on disease phenotype and outcome remain unknown. We set out to investigate the role of intestinal epithelial DNAm in CD pathogenesis.

The bacterial lysate OM-85 engages Toll-like receptors 2 and 4 triggering an immunomodulatory gene signature in human myeloid cells.

OM-85 is a bacterial lysate used in clinical practice to reduce duration and frequency of recurrent respiratory tract infections. Whereas knowledge of its regulatory effects in vivo has substantially advanced, the mechanisms of OM-85 sensing remain inadequately addressed. Here, we show that the immune response to OM-85 in the mouse is largely mediated by myeloid immune cells through Toll-like receptor (TLR) 4 in vitro and in vivo.

Retinoic acid receptor activation reprograms senescence response and enhances anti-tumor activity of natural killer cells.

Cellular senescence can exert dual effects in tumors, either suppressing or promoting tumor progression. The senescence-associated secretory phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, favoring tumor-suppressive SASP factors over tumor-promoting ones.

Myc controls NK cell development, IL-15-driven expansion, and translational machinery.

MYC is a pleiotropic transcription factor involved in cancer, cell proliferation, and metabolism. Its regulation and function in NK cells, which are innate cytotoxic lymphocytes important to control viral infections and cancer, remain poorly defined. Here, we show that mice deficient for Myc in NK cells presented a severe reduction in these lymphocytes.

SHP-1 localization to the activating immune synapse promotes NK cell tolerance in MHC class I deficiency.

Natural killer (NK) cells recognize virally infected cells and tumors. NK cell function depends on balanced signaling from activating receptors, recognizing products from tumors or viruses, and inhibitory receptors (such as KIR/Ly49), which recognize major histocompatibility complex class I (MHC-I) molecules. KIR/Ly49 signaling preserves tolerance to self but also conveys reactivity toward MHC-I-low target cells in a process known as NK cell education.

Concomitant deletion of Ptpn6 and Ptpn11 in T cells fails to improve anticancer responses.

Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as PD-1. Blockade of PD-1 leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase PTPN11 (known as SHP-2) is essential for PD-1 signaling in T cells, suggesting functional redundancy with the homologous phosphatase PTPN6 (SHP-1).

FOXC2 controls adult lymphatic endothelial specialization, function, and gut lymphatic barrier preventing multiorgan failure.

The mechanisms maintaining adult lymphatic vascular specialization throughout life and their role in coordinating inter-organ communication to sustain homeostasis remain elusive. We report that inactivation of the mechanosensitive transcription factor in adult lymphatic endothelium leads to a stepwise intestine-to-lung systemic failure. loss compromised the gut epithelial barrier, promoted dysbiosis and bacterial translocation to peripheral lymph nodes, and increased circulating levels of purine metabolites and angiopoietin-2.

NLRC5 promotes transcription of genes and Vγ9Vδ2 T cell-mediated killing.

BTN3A molecules-BTN3A1 in particular-emerged as important mediators of Vγ9Vδ2 T cell activation by phosphoantigens. These metabolites can originate from infections, e.g.

Regulatory Factor X 7 and its Potential Link to Lymphoid Cancers.

Alterations in the Regulatory factor X 7 (RFX7) gene have recurrently been reported in lymphoid cancers. Uncharacterized until recently, this transcription factor regulates genes important for ciliogenesis and for limiting cellular metabolic activity. Here we discuss these observations and conjecture on the links between the reported functions of RFX7 and its potential role in lymphoid cancers, encouraging future studies in these directions.

SHP-2 in Lymphocytes' Cytokine and Inhibitory Receptor Signaling.

Somewhat counterintuitively, the tyrosine phosphatase SHP-2 (SH2 domain-containing protein tyrosine phosphatase-2) is crucial for the activation of extracellular signal-regulated kinase (ERK) downstream of various growth factor receptors, thereby exerting essential developmental functions. This phosphatase also deploys proto-oncogenic functions and specific inhibitors have recently been developed. With respect to the immune system, the role of SHP-2 in the signaling of cytokines relevant for myelopoiesis and myeloid malignancies has been intensively studied.

Shp-2 is critical for ERK and metabolic engagement downstream of IL-15 receptor in NK cells.

The phosphatase Shp-2 was implicated in NK cell development and functions due to its interaction with NK inhibitory receptors, but its exact role in NK cells is still unclear. Here we show, using mice conditionally deficient for Shp-2 in the NK lineage, that NK cell development and responsiveness are largely unaffected. Instead, we find that Shp-2 serves mainly to enforce NK cell responses to activation by IL-15 and IL-2.

The transcription factor Rfx7 limits metabolism of NK cells and promotes their maintenance and immunity.

Regulatory factor X 7 (Rfx7) is an uncharacterized transcription factor belonging to a family involved in ciliogenesis and immunity. Here, we found that deletion of Rfx7 leads to a decrease in natural killer (NK) cell maintenance and immunity in vivo. Genomic approaches showed that Rfx7 coordinated a transcriptional network controlling cell metabolism.

Shp-2 Is Dispensable for Establishing T Cell Exhaustion and for PD-1 Signaling In Vivo.

In chronic infection and cancer, T cells acquire a dysfunctional state characterized by the expression of inhibitory receptors. In vitro studies implicated the phosphatase Shp-2 downstream of these receptors, including PD-1. However, whether Shp-2 is responsible in vivo for such dysfunctional responses remains elusive.

The regulatory network behind MHC class I expression.

The MHC class I pathway, presenting endogenously derived peptides to T lymphocytes, is hijacked in many pathological conditions. This affects MHC class I levels and peptide presentation at the cell surface leading to immune escape of cancer cells or microbes. It is therefore important to identify the molecular mechanisms behind MHC class I expression, processing and antigen presentation.

OM-85 is an immunomodulator of interferon-β production and inflammasome activity.

The inflammasome-IL-1 axis and type I interferons (IFNs) have been shown to exert protective effects upon respiratory tract infections. Conversely, IL-1 has also been implicated in inflammatory airway pathologies such as asthma and chronic obstructive pulmonary disease (COPD). OM-85 is a bacterial extract with proved efficacy against COPD and recurrent respiratory tract infections, a cause of co-morbidity in asthmatic patients.

Emerging Major Histocompatibility Complex Class I-Related Functions of NLRC5.

Recent evidence demonstrates a key role for the nucleotide-binding oligomerization domain-like receptor (NLR) family member NLRC5 (NLR family, CARD domain containing protein 5) in the transcriptional regulation of major histocompatibility complex (MHC) class I and related genes. Detailed information on NLRC5 target genes in various cell types and conditions is emerging. Thanks to its analogy to CIITA (class II major MHC transactivator), a NLR family member known for over 20 years to be the master regulator of MHC class II gene transcription, also the molecular mechanisms underlying NLRC5 function are being rapidly unraveled.

NLRC5, a promising new entry in tumor immunology.

The recent use of T cell-based cancer immunotherapies, such as adoptive T-cell transfer and checkpoint blockade, yields increasing clinical benefit to patients with different cancer types. However, decrease of MHC class I expression is a common mechanism transformed cells take advantage of to evade CD8(+) T cell-mediated antitumor responses, negatively impacting on the outcome of immunotherapies. Hence, there is an urgent need to develop novel approaches to overcome this limitation.

T Cell Priming by Activated Nlrc5-Deficient Dendritic Cells Is Unaffected despite Partially Reduced MHC Class I Levels.

NLRC5, a member of the NOD-like receptor (NLR) protein family, has recently been characterized as the master transcriptional regulator of MHCI molecules in lymphocytes, in which it is highly expressed. However, its role in activated dendritic cells (DCs), which are instrumental to initiate T cell responses, remained elusive. We show in this study that, following stimulation of DCs with inflammatory stimuli, not only did NLRC5 level increase, but also its importance in directing MHCI transcription.

NLRC5 shields T lymphocytes from NK-cell-mediated elimination under inflammatory conditions.

NLRC5 is a transcriptional regulator of MHC class I (MHCI), which maintains high MHCI expression particularly in T cells. Recent evidence highlights an important NK-T-cell crosstalk, raising the question on whether NLRC5 specifically modulates this interaction. Here we show that NK cells from Nlrc5-deficient mice exhibit moderate alterations in inhibitory receptor expression and responsiveness.

Strengthening of Porcelain Provided by Resin Cements and Flowable Composites.

This study evaluated the effect of mechanical properties of resin-based luting agents on the strength of resin-coated porcelain. The luting agents tested were two flowable resin composites (Filtek Z350 Flow and Tetric-N Flow), a light-cured resin cement (Variolink Veneer [VV]), and a dual-cured resin cement (Variolink II) in either light-cured (base paste) or dual-cured (base + catalyst pastes [VD]) mode. Flexural strength (σf) and modulus of elasticity (Ef) of the luting agents were measured in three-point bending mode (n=5).

NLRC5 exclusively transactivates MHC class I and related genes through a distinctive SXY module.

MHC class II (MHCII) genes are transactivated by the NOD-like receptor (NLR) family member CIITA, which is recruited to SXY enhancers of MHCII promoters via a DNA-binding "enhanceosome" complex. NLRC5, another NLR protein, was recently found to control transcription of MHC class I (MHCI) genes. However, detailed understanding of NLRC5's target gene specificity and mechanism of action remained lacking.

NLRC5, at the Heart of Antigen Presentation.

Nucleotide-binding domain and leucine-rich repeat containing receptors (NLRs) are intracellular proteins mainly involved in pathogen recognition, inflammatory responses, and cell death. Until recently, the function of the family member NLR caspase recruitment domain (CARD) containing 5 (NLRC5) has been a matter of debate. It is now clear that NLRC5 acts as a transcriptional regulator of the major-histocompatibility complex class I.