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. NLRC5 has been recently described as a key transcriptional regulator controlling expression of MHC class I molecules. In this commentary, we summarize and put into perspective a study by Rodriguez and colleagues recently published in Oncoimmunology, addressing the role of NLRC5 in melanoma. The authors demonstrate that NLRC5 overexpression in B16 melanoma allows to recover MHC class I expression, rising tumor immunogenicity and counteracting immune evasion. Possible ways of manipulating NLRC5 activity in tumors will be discussed. Highlighting the therapeutic potential of modulating NLRC5 levels, this publication also encourages evaluation of NLRC5, and by extension MHC class I pathway, as clinical biomarker to select personalized immunotherapeutic strategies

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. We therefore asked whether OM-85 affects the above-mentioned innate immune pathways. Here we show that OM-85 induced interferon-β through the Toll-like receptor adaptors Trif and MyD88 in bone marrow-derived dendritic cells. Moreover, it exerted a dual role on IL-1 production; on the one hand, it upregulated proIL-1β and proIL-1α levels in a MyD88-dependent manner without activating the inflammasome. On the other hand, it repressed IL-1β secretion induced by alum, a well-known NLRP3 activator. In vivo, OM-85 diminished the recruitment of inflammatory cells in response to peritoneal alum challenge. Our findings therefore suggest that OM-85 favors a protective primed state, while dampening inflammasome activation in specific conditions. Taken together, these data bring new insights into the mechanisms of OM-85 action on innate immune pathways and suggest potential explanations for its efficacy in the treatment of virus-induced airway diseases

Influence of intra-articular injections of sodium hyaluronate on clinical features and synovial fluid nitric oxide levels of temporomandibular osteoarthritis

Objective: This study was designed to assess the effect of intra-articular injection of sodium hyaluronate (SH) on clinical findings of temporomandibular osteoarthritis (OA) and on synovial fluid (SF) levels of nitric oxide (NO). Methods: Twenty seven patients (7 men, 20 women, mean (SD) age 53.9 (11.8) years) with OA of the temporomandibular joint were randomly allocated to receive an injection of either SH (2ml, Hyalgan®, Fidia SpA, Abano T., P.M. 500-700.000, 20mg/2ml; once a week for 5 weeks) or a Ringer's lactate solution (once a week for 3 weeks). Clinical evaluation was done before each procedure, and at 1 week, 1, 3 and 6 months post-injection. Intensity of temporomandibular joint pain, jaw function, maximal mouth opening and lateral jaw movements were recorded at each visit. NO was measured on SF collected by rinsing the joint with saline 1 ml before the treatment. Results: Injection of SH caused significant improvement in the main clinical symptoms until the last follow-up which was carried out 6 months after last injection. Among patients who received SH injection, those who reached a good outcome showed the lowest basal levels of NO. Conclusions: The results of this study showed that intra-articular injections of SH lead to a lasting improvement in the clinical symptoms of temporomandibular OA. Furthermore, our findings suggest that low NO levels in SF are related to a better outcome of temporomandibular OA among patients treated with SH intra-articular injection

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. Despite markedly reduced mRNA and intracellular H2-K levels, we unexpectedly observed nearly normal H2-K surface display in Nlrc5(-/-) DCs. Importantly, this discrepancy between a strong intracellular and a mild surface defect in H2-K levels was observed also in DCs with H2-K transcription defects independent of Nlrc5. Hence, alongside with demonstrating the importance of NLRC5 in MHCI transcription in activated DCs, we uncover a general mechanism counteracting low MHCI surface expression. In agreement with the decreased amount of neosynthesized MHCI, Nlrc5(-/-) DCs exhibited a defective capacity to display endogenous Ags. However, neither T cell priming by endogenous Ags nor cross-priming ability was substantially affected in activated Nlrc5(-/-) DCs. Altogether, these data show that Nlrc5 deficiency, despite significantly affecting MHCI transcription and Ag display, is not sufficient to hinder T cell activation, underlining the robustness of the T cell priming process by activated DCs

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. To address this, we generated T cell-specific Shp-2-deficient mice. These mice did not show differences in controlling chronic viral infections. In this context, Shp-2-deleted CD8 <sup>+</sup> T lymphocytes expanded moderately better but were less polyfunctional than control cells. Mice with Shp-2-deficient T cells also showed no significant improvement in controlling immunogenic tumors and responded similarly to controls to α-PD-1 treatment. We therefore showed that Shp-2 is dispensable in T cells for globally establishing exhaustion and for PD-1 signaling in vivo. These results reveal the existence of redundant mechanisms downstream of inhibitory receptors and represent the foundation for defining these relevant molecular events

Total temporomandibular joint prosthesis as a surgical option for severe mouth opening restriction. A case report of a bilateral intervention

Temporomandibular disorders (TMD) are a heterogeneous group of pathologies affecting the temporomandibular joint (TMJ) and/or the masticator muscles, characterized by a molteplicity of signs and symptoms, the most common of which are pain localized in the preauricular area and/or in the masticatory muscles; jaw motion abnormalities; articular sounds, such as click and/or crepitus, during mandibular movements (1). A specific etiolpathogenesis is detectable in a minority of cases, since the occurrence of TMD symptoms is often..

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. Interestingly, NLRC5 expression in T cells is required to protect them from NK-cell-mediated elimination upon inflammation. Using T-cell-specific Nlrc5-deficient mice, we show that NK cells surprisingly break tolerance even towards 'self' Nlrc5-deficient T cells under inflammatory conditions. Furthermore, during chronic LCMV infection, the total CD8(+) T-cell population is severely decreased in these mice, a phenotype reverted by NK-cell depletion. These findings strongly suggest that endogenous T cells with low MHCI expression become NK-cell targets, having thus important implications for T-cell responses in naturally or therapeutically induced inflammatory conditions

Psychobiological, Clinical, and Sociocultural Factors That Influence Black Women Seeking Treatment for Infertility: A Mixed-methods Study

OBJECTIVE: To provide a comprehensive and multidimensional description and conceptualization of the experiences of Black women seeking treatment for infertility. DESIGN: Convergent parallel mixed-methods study combining retrospective chart review data and semistructured interview data. SETTING: Private infertility clinic. PATIENT(S): African American/Black women between 18 and 44 years of age who presented for an initial infertility evaluation with a male partner between January 2015 and September 2019 at an infertility clinic in the metropolitan Washington D.C. area. INTERVENTION(S): None MAIN OUTCOME(S): Treatment seeking. MEASURE(S): Psychobiological, clinical, and sociocultural factors. RESULT(S): Along with the psychobiological, clinical, and sociocultural domains, we understood that Black women who sought treatment for infertility were older and overweight, had complex gynecological diagnoses, and experienced infertility for long periods of time. The delay in seeking treatment was possibly because of a low perceived risk of infertility, poor understanding of treatment options, inadequate referral patterns of primary care providers, and limited social support. Further, Black women experienced delays in seeking treatment because they attempted lifestyle-based self-interventions before considering medical interventions. Facilitators to care included psychological distress, complex gynecological medical history, and finding culturally competent providers. CONCLUSION(S): The study findings show that Black women in the United States are vulnerable to disparities in healthcare delivery, especially within reproductive endocrinology. Our findings highlight areas where Black women are experiencing missed opportunities for teaching, early identification, and early referrals for infertility-related concerns. Future studies should seek to reduce barriers to infertility treatment at the clinical and policy levels

NLRC5 promotes transcription of BTN3A1-3 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. with Mycobacterium tuberculosis, or by alterations in cellular metabolism. Despite the growing interest in the BTN3A genes and their high expression in immune cells and various cancers, little is known about their transcriptional regulation. Here we show that these genes are induced by NLRC5, a regulator of MHC class I gene transcription, through an atypical regulatory motif found in their promoters. Accordingly, a robust correlation between NLRC5 and BTN3A gene expression was found in healthy, in M. tuberculosis-infected donors' blood cells, and in primary tumors. Moreover, forcing NLRC5 expression promoted Vγ9Vδ2 T-cell-mediated killing of tumor cells in a BTN3A-dependent manner. Altogether, these findings indicate that NLRC5 regulates the expression of BTN3A genes and hence open opportunities to modulate antimicrobial and anticancer immunity