Role of MAIT cells in gastrointestinal tract bacterial infections in humans: More than a gut feeling.

Mucosa-associated invariant T (MAIT) cells are the largest population of unconventional T cells in humans. These antimicrobial T cells are poised with rapid effector responses following recognition of the cognate riboflavin (vitamin B2)-like metabolite antigens derived from microbial riboflavin biosynthetic pathway. Presentation of this unique class of small molecule metabolite antigens is mediated by the highly evolutionarily conserved major histocompatibility complex class I-related protein. In humans, MAIT cells are widely found along the upper and lower gastrointestinal tracts owing to their high expression of chemokine receptors and homing molecules directing them to these tissue sites. In this review, we discuss recent findings regarding the roles MAIT cells play in various gastrointestinal bacterial infections, and how their roles appear to differ depending on the etiological agents and the anatomical location. We further discuss the potential mechanisms by which MAIT cells contribute to pathogen control, orchestrate adaptive immunity, as well as their potential contribution to inflammation and tissue damage during gastrointestinal bacterial infections, and the ensuing tissue repair following resolution. Finally, we propose and discuss the use of the emerging three-dimensional organoid technology to test different hypotheses regarding the role of MAIT cells in gastrointestinal bacterial infections, inflammation, and immunity.

Phosphorus metabolism in the brain of cognitively normal midlife individuals at risk for Alzheimer's disease.

Background: Neurometabolic abnormalities and amyloid-beta plaque deposition are important early pathophysiologic changes in Alzheimer's disease (AD). This study investigated the relationship between high-energy phosphorus-containing metabolites, glucose uptake, and amyloid plaque using phosphorus magnetic resonance spectroscopy (31P-MRS) and positron emission tomography (PET). Methods: We measured 31P-MRS, fluorodeoxyglucose (FDG)-PET, and Pittsburgh Compound B (PiB)-PET in a cohort of 20 cognitively normal middle-aged adults at risk for AD. We assessed 31P-MRS reliability by scanning a separate cohort of 13 healthy volunteers twice each. We calculated the coefficient-of-variation (CV) of metabolite ratios phosphocreatine-to-adenosine triphosphate (PCr/α-ATP), inorganic phosphate (Pi)-to-α-ATP, and phosphomonoesters-to-phosphodiesters (PME/PDE), and pH in pre-defined brain regions. We performed linear regression analysis to determine the relationship between 31P measurements and tracer uptake, and Dunn's multiple comparison tests to investigate regional differences in phosphorus metabolism. Finally, we performed linear regression analysis on 31P-MRS measurements in both cohorts to investigate the relationship of phosphorus metabolism with age. Results: Most regional 31P metabolite ratio and pH inter- and intra-day CVs were well below 10%. There was an inverse relationship between FDG-SUV levels and metabolite ratios PCr/α-ATP, Pi/α-ATP, and PME/PDE in several brain regions in the AD risk group. There were also several regional differences among 31P metabolites and pH in the AD risk group including elevated PCr/α-ATP, depressed PME/PDE, and elevated pH in the temporal cortices. Increased PCr/α-ATP throughout the brain was associated with aging. Conclusions: Phosphorus spectroscopy in the brain can be performed with high repeatability. Phosphorus metabolism varies with region and age, and is related to glucose uptake in adults at risk for AD. Phosphorus spectroscopy may be a valuable approach to study early changes in brain energetics in high-risk populations.

IL7RA single nucleotide polymorphisms are associated with the size and function of the MAIT cell population in treated HIV-1 infection.

MAIT cells are persistently depleted and functionally exhausted in HIV-1-infected patients despite long-term combination antiretroviral therapy (cART). IL-7 treatment supports MAIT cell reconstitution in vivo HIV-1-infected individuals and rescues their functionality in vitro. Single-nucleotide polymorphisms (SNPs) of the IL-7RA gene modulate the levels of soluble(s)IL-7Rα (sCD127) levels and influence bioavailability of circulating IL-7. Here we evaluate the potential influence of IL-7RA polymorphisms on MAIT cell numbers and function in healthy control (HC) subjects and HIV-1-infected individuals on long-term cART. Our findings indicate that IL-7RA haplotype 2 (H2*T), defined as T-allele carriers at the tagging SNP rs6897932, affects the size of the peripheral blood MAIT cell pool, as well as their production of cytokines and cytolytic effector proteins in response to bacterial stimulation. H2*T carriers had lower sIL-7Rα levels and higher MAIT cell frequency with enhanced functionality linked to higher expression of MAIT cell-associated transcription factors. Despite an average of 7 years on suppressive cART, MAIT cell levels and function in HIV-1-infected individuals were still significantly lower than those of HC. Notably, we observed a significant correlation between MAIT cell levels and cART duration only in HIV-1-infected individuals carrying IL-7RA haplotype 2. Interestingly, treatment with sIL-7Rα in vitro suppressed IL-7-dependent MAIT cell proliferation and function following cognate stimulations. These observations suggest that sIL-7Rα levels may influence MAIT cell numbers and function in vivo by limiting IL-7 bioavailability to MAIT cells. Collectively, these observations suggest that IL-7RA polymorphisms may play a significant role in MAIT cell biology and influence MAIT cells recovery in HIV-1 infection. The potential links between IL7RA polymorphisms, MAIT cell immunobiology, and HIV-1 infection warrant further studies going forward.

Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities.

Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-ß, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.

MAIT Cell Loss and Reconstitution in HIV-1 Disease.

Mucosa-associated invariant T (MAIT) cells are unconventional innate-like T cells that recognize microbial riboflavin-related metabolites presented by the evolutionarily conserved MHC class I-related (MR1) molecule. MAIT cells are abundant in circulation and mucosal tissues and are poised to mount rapid effector responses against diverse microbial organisms. Despite the absence of virally encoded riboflavin-related metabolite antigens, MAIT cells can respond to viral infections in an MR1-independent and cytokine-dependent manner. In chronic HIV-1 infection, MAIT cells are persistently depleted and functionally exhausted. Long-term effective combination antiretroviral therapy can only partially rescue MAIT cell numbers and dysfunction. Our understanding of the mechanisms underlying MAIT cell loss in HIV-1 infection is still incomplete, and to date, few effective strategies to recover their loss in humans are available. Here, we review current knowledge concerning the mechanisms of MAIT cell responses and loss in different stages of HIV-1 infection and how we may potentially develop strategies to restore these cells in the clinical setting. We further discuss novel strategies that may aid future investigations into MAIT cell immunobiology in HIV-1 infection, including the potential use of three-dimensional organoid models to dissect the mechanisms of MAIT cell depletion and to explore interventions that may restore their numbers and functionality.

Electrophysiological evidence for the integral nature of tone in Mandarin spoken word recognition.

Current models of spoken word recognition have been predominantly based on studies of Indo-European languages. As a result, less is known about the recognition processes involved in the perception of tonal languages (e.g., Mandarin Chinese), and the role of lexical tone in speech perception. One view is that words in tonal languages are processed phonologically through individual segments, while another view is that they are processed lexically as a whole. Moreover, a recent study claimed to be the first to discover an early phonological processing stage in Mandarin (Huang et al., 2014). There seems to be a lack of investigations concerning tonal languages, as no clear conclusions have been reached about the nature of tonal processes, or a model of spoken word recognition that best incorporates lexical tone. The current study addressed these issues by presenting 18 native Mandarin speakers with aural sentences with medial target words. These either matched or mismatched the preceding visually presented sentences with medial target words (e.g, /jia1/home). Violation conditions involved target words that differed in the following ways: tone violation, where only the tone was different (e.g., /jia4/"price"), onset violation, where only the onset was different (e.g., /xia1/"shrimp"), and syllable violation, where both the tone and the onset were different (e.g., /tang2/"candy"). We did not find evidence for an early phonological processing stage in Mandarin. Instead, our findings indicate that Mandarin syllables are processed incrementally through phonological segments and that tone is strongly associated with lexical access. These results are discussed with respect to modifications for existing models in spoken word recognition to incorporate the processes involved with tonal language recognition.

Role models and the psychological characteristics that buffer low-socioeconomic-status youth from cardiovascular risk.

Little is understood about why some youth from low-socioeconomic-status (SES) environments exhibit good health despite adversity. This study tested whether role models and "shift-and-persist" approaches (reframing stressors more benignly while persisting with future optimism) protect low-SES youth from cardiovascular risk. A total of 163 youth, ages 13-16, completed role model interviews and shift-and-persist measures while cholesterol and inflammatory markers, interleukin-6 (IL-6), and C-reactive protein were assessed. Low-SES youth with supportive role models had lower IL-6. Low-SES youth high in shift-and-persist also had lower IL-6. Shift-and-persist partially mediated the interaction of SES and role models on IL-6. Benefits were not found among high-SES youth. Identifying psychological buffers in low-SES youth has implications for health disparities.