Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19.

A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multiorgan failure and death. Overall, these findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19. Our study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling.

Assessing accuracy of resonances obtained with reassigned spectrograms from the "ground truth" of physical vocal tract models.

The reassigned spectrogram (RS) has emerged as the most accurate way to infer vocal tract resonances from the acoustic signal [Shadle, Nam, and Whalen (2016). "Comparing measurement errors for formants in synthetic and natural vowels," J. Acoust. Soc. Am. 139(2), 713-727]. To date, validating its accuracy has depended on formant synthesis for ground truth values of these resonances. Synthesis is easily controlled, but it has many intrinsic assumptions that do not necessarily accurately realize the acoustics in the way that physical resonances would. Here, we show that physical models of the vocal tract with derivable resonance values allow a separate approach to the ground truth, with a different range of limitations. Our three-dimensional printed vocal tract models were excited by white noise, allowing an accurate determination of the resonance frequencies. Then, sources with a range of fundamental frequencies were implemented, allowing a direct assessment of whether RS avoided the systematic bias towards the nearest strong harmonic to which other analysis techniques are prone. RS was indeed accurate at fundamental frequencies up to 300 Hz; above that, accuracy was somewhat reduced. Future directions include testing mechanical models with the dimensions of children's vocal tracts and making RS more broadly useful by automating the detection of resonances.

Expression of visfatin in gingival crevicular fluid and gingival tissues in different periodontal conditions: a cross-sectional study.

BACKGROUND: Studies have shown that visfatin is an inflammatory factor closely related to periodontitis. We examined the levels of visfatin in gingival crevicular fluid (GCF) and gingival tissues under different periodontal conditions, in order to provide more theoretical basis for exploring the role of visfatin in the pathogenesis of periodontitis. METHODS: We enrolled 87 subjects, with 43 in the chronic periodontitis (CP) group, 21 in the chronic gingivitis (CG) group, and 23 in the periodontal health (PH) group. Periodontal indexes (PD, AL, PLI, and BI) were recorded. GCF samples were collected for visfatin quantification, and gingival tissues were assessed via immunohistochemical staining. RESULTS: Visfatin levels in GCF decreased sequentially from CP to CG and PH groups, with statistically significant differences (P < 0.05). The CP group exhibited the highest visfatin levels, while the PH group had the lowest. Gingival tissues showed a similar trend, with significant differences between groups (P < 0.001). Periodontal indexes were positively correlated with visfatin levels in both GCF and gingival tissues (P < 0.001). A strong positive correlation was observed between visfatin levels in GCF and gingival tissues (rs = 0.772, P < 0.001). CONCLUSION: Greater periodontal destruction corresponded to higher visfatin levels in GCF and gingival tissues, indicating their potential collaboration in damaging periodontal tissues. Visfatin emerges as a promising biomarker for periodontitis and may play a role in its pathogenesis.

An acoustic study of Cantonese alaryngeal speech in different speaking conditions.

Esophageal (ES) speech, tracheoesophageal (TE) speech, and the electrolarynx (EL) are common methods of communication following the removal of the larynx. Our recent study demonstrated that intelligibility may increase for Cantonese alaryngeal speakers using clear speech (CS) compared to their everyday "habitual speech" (HS), but the reasoning is still unclear [Hui, Cox, Huang, Chen, and Ng (2022). Folia Phoniatr. Logop. 74, 103-111]. The purpose of this study was to assess the acoustic characteristics of vowels and tones produced by Cantonese alaryngeal speakers using HS and CS. Thirty-one alaryngeal speakers (9 EL, 10 ES, and 12 TE speakers) read The North Wind and the Sun passage in HS and CS. Vowel formants, vowel space area (VSA), speaking rate, pitch, and intensity were examined, and their relationship to intelligibility were evaluated. Statistical models suggest that larger VSAs significantly improved intelligibility, but slower speaking rate did not. Vowel and tonal contrasts did not differ between HS and CS for all three groups, but the amount of information encoded in fundamental frequency and intensity differences between high and low tones positively correlated with intelligibility for TE and ES groups, respectively. Continued research is needed to understand the effects of different speaking conditions toward improving acoustic and perceptual characteristics of Cantonese alaryngeal speech.

Refining and extending measures for fricative spectra, with special attention to the high-frequency rangea).

Fricatives have noise sources that are filtered by the vocal tract and that typically possess energy over a much broader range of frequencies than observed for vowels and sonorant consonants. This paper introduces and refines fricative measurements that were designed to reflect underlying articulatory and aerodynamic conditions These show differences in the pattern of high-frequency energy for sibilants vs non-sibilants, voiced vs voiceless fricatives, and non-sibilants differing in place of articulation. The results confirm the utility of a spectral peak measure (FM) and low-mid frequency amplitude difference (AmpD) for sibilants. Using a higher-frequency range for defining FM for female voices for alveolars is justified; a still higher range was considered and rejected. High-frequency maximum amplitude (Fh) and amplitude difference between low- and higher-frequency regions (AmpRange) capture /f-θ/ differences in English and the dynamic amplitude range over the entire spectrum. For this dataset, with spectral information up to 15 kHz, a new measure, HighLevelD, was more effective than previously used LevelD and Slope in showing changes over time within the frication. Finally, isolated words and connected speech differ. This work contributes improved measures of fricative spectra and demonstrates the necessity of including high-frequency energy in those measures.

Nanoporous Gold Ring-Integrated Photothermal Intraocular Lens for Active Prevention of Posterior Capsular Opacification.

Posterior capsular opacification (PCO) is the leading complication after cataract surgery, and is mainly induced by the proliferation and migration of residual lens epithelial cells (LECs). Although numerous attempts have been made to reduce the incidence of PCO, this complication remains a critical challenge in postoperative visual recovery. This study aims to report a functionalized intraocular lens (R-IOL) with a region-confined photothermal effect for the active prevention of PCO after implantation. The outer rim of R-IOL (non-optical area) is decorated with a nanoporous gold (NPG) ring, which can effectively eliminate the LECs around R-IOL, ultimately inhibiting the migration of LECs from the periphery to the visual axis center in the initial stage, and preventing the subsequent PCO. Furthermore, the mechanism of LECs elimination can be attributed to apoptosis induced by mild photothermal therapy. After in vivo implantation for 30 days, PCO is rarely observed in the R-IOL group, whereas the considerably higher incidence of PCO (75%) is found in the pristine IOL (P-IOL) group. The region-confined photothermal effect based on NPG not only provides an active strategy to effectively prevent PCO, but also introduces new opportunities for the treatment of undesirable hyperplasia.

Broadening the genotypic and phenotypic spectrum of MAF in three Chinese Han congenital cataracts families.

Pathogenic variants in the v-maf avian musculoaponeurotic fibrosarcoma oncogene homologue (MAF) encoding a transcription factor (from a unique subclass of basic leucine zipper transcription factors) are associated with isolated congenital cataracts (CCs) and Aymé-Gripp syndrome (AYGRPS). We collected detailed disease histories from, and performed comprehensive ophthalmic and systemic examinations in 269 patients with CCs; we then performed whole-exome sequencing. Pathogenicity assessments were evaluated using multiple predictive tools. The clinical validities of the reported gene-disease relationships for MAF genes (MAF-CCs and MAF-AYGRPS) were assessed using the ClinGen gene curation framework. We identified two novel (c.173C>A, p.Thr58Asn and c.947T>C, p. Leu316Pro) variants and one known (c.173C>T, p.Thr58Ile) MAF missense variant in three patients. We described novel phenotypes including cleft palate, macular hypoplasia, and retinal neovascularization in the peripheral avascular area and analyzed the genotype-phenotype correlations. We demonstrated associations of variants in the MAF C-terminal DNA-binding domain with CCs and associations of variants in the N-terminal transactivation domain of MAF with AYGRPS. We thus expand the genotypic and phenotypic spectrum of the MAF gene. The ClinGen gene curation framework results suggested that variants in different domains of MAF are associated with different diseases.

Formants are easy to measure; resonances, not so much: Lessons from Klatt (1986).

Formants in speech signals are easily identified, largely because formants are defined to be local maxima in the wideband sound spectrum. Sadly, this is not what is of most interest in analyzing speech; instead, resonances of the vocal tract are of interest, and they are much harder to measure. Klatt [(1986). in Proceedings of the Montreal Satellite Symposium on Speech Recognition, 12th International Congress on Acoustics, edited by P. Mermelstein (Canadian Acoustical Society, Montreal), pp. 5-7] showed that estimates of resonances are biased by harmonics while the human ear is not. Several analysis techniques placed the formant closer to a strong harmonic than to the center of the resonance. This "harmonic attraction" can persist with newer algorithms and in hand measurements, and systematic errors can persist even in large corpora. Research has shown that the reassigned spectrogram is less subject to these errors than linear predictive coding and similar measures, but it has not been satisfactorily automated, making its wider use unrealistic. Pending better techniques, the recommendations are (1) acknowledge limitations of current analyses regarding influence of F0 and limits on granularity, (2) report settings more fully, (3) justify settings chosen, and (4) examine the pattern of F0 vs F1 for possible harmonic bias.

The Effect of Clear Speech on Cantonese Alaryngeal Speakers' Intelligibility.

BACKGROUND/AIM: The purpose of this study was to provide preliminary data concerning the effect of clear speech (CS) on Cantonese alaryngeal speakers' intelligibility. METHODS: Voice recordings of 11 sentences randomly selected from the Cantonese Sentence Intelligibility Test (CSIT) were obtained from 31 alaryngeal speakers (9 electrolarynx [EL] users, 10 esophageal speakers and 12 tracheoesophageal [TE] speakers) in habitual speech (HS) and CS. Two naïve listeners orthographically transcribed a total of 1,364 sentences. RESULTS: Significant effects of speaking condition on speaking rate and CSIT scores were observed, but no significant effect of alaryngeal communication methods was noted. CS was significantly slower than HS by 0.78 syllables/s. Esophageal speakers demonstrated the slowest speech rate when using CS, while EL users demonstrated the largest decrease in speaking rate when using CS compared to HS. TE speakers had the highest CSIT scores in HS (listener 1 = 81.4%; listener 2 = 81.3%), and esophageal speakers had the highest CSIT scores in CS (listener 1 = 87.5%; listener 2 = 89.7%). EL users experienced the largest increase in intelligibility while using CS compared to HS (9.1%) followed by esophageal speakers (8.9%) and TE speakers (1.4%). CONCLUSION: Preliminary data indicate that CS may significantly affect Cantonese alaryngeal speakers' speaking rate and intelligibility. However, intelligibility appeared to vary considerably across speakers. Further research involving larger, heterogeneous groups of speakers and listeners alongside longer and more refined CS training protocols should be conducted to confirm that CS can improve Cantonese alaryngeal speakers' intelligibility.

Comparison of auto-contouring and hand-contouring of ultrasound images of the tongue surface.

Contours traced by trained phoneticians have been considered to be the most accurate way to identify the midsagittal tongue surface from ultrasound video frames. In this study, inter-measurer reliability was evaluated using measures that quantified both how closely human-placed contours approximated each other as well as how consistent measurers were in defining the start and end points of contours. High reliability across three measurers was found for all measures, consistent with treating contours placed by trained phoneticians as the 'gold standard.' However, due to the labour-intensive nature of hand-placing contours, automatic algorithms that detect the tongue surface are increasingly being used to extract tongue-surface data from ultrasound videos. Contours placed by six automatic algorithms (SLURP, EdgeTrak, EPCS, and three different configurations of the algorithm provided in Articulate Assistant Advanced) were compared to human-placed contours, with the same measures used to evaluate the consistency of the trained phoneticians. We found that contours defined by SLURP, EdgeTrak, and two of the AAA configurations closely matched the hand-placed contours along sections of the image where the algorithms and humans agreed that there was a discernible contour. All of the algorithms were much less reliable than humans in determining the anterior (tongue-tip) edge of tongue contours. Overall, the contours produced by SLURP, EdgeTrak, and AAA should be useable in a variety of clinical applications, subject to spot-checking. Additional practical considerations of these algorithms are also discussed.

Dexmedetomidine post-treatment attenuates cardiac ischaemia/reperfusion injury by inhibiting apoptosis through HIF-1α signalling.

Hypoxia-inducible factor 1α (HIF-1α) plays a critical role in the apoptotic process during cardiac ischaemia/reperfusion (I/R) injury. This study aimed to investigate whether post-treatment with dexmedetomidine (DEX) could protect against I/R-induced cardiac apoptosis in vivo and in vitro via regulating HIF-1α signalling pathway. Rat myocardial I/R was induced by occluding the left anterior descending artery for 30 minutes followed by 6-hours reperfusion, and cardiomyocyte hypoxia/reoxygenation (H/R) was induced by oxygen-glucose deprivation for 6 hours followed by 3-hours reoxygenation. Dexmedetomidine administration at the beginning of reperfusion or reoxygenation attenuated I/R-induced myocardial injury or H/R-induced cell death, alleviated mitochondrial dysfunction, reduced the number of apoptotic cardiomyocytes, inhibited the activation of HIF-1α and modulated the expressions of apoptosis-related proteins including BCL-2, BAX, BNIP3, cleaved caspase-3 and cleaved PARP. Conversely, the HIF-1α prolyl hydroxylase-2 inhibitor IOX2 partly blocked DEX-mediated cardioprotection both in vivo and in vitro. Mechanistically, DEX down-regulated HIF-1α expression at the post-transcriptional level and inhibited the transcriptional activation of the target gene BNIP3. Post-treatment with DEX protects against cardiac I/R injury in vivo and H/R injury in vitro. These effects are, at least in part, mediated via the inhibition of cell apoptosis by targeting HIF-1α signalling.

Conjunctival microvascular responses to anti-inflammatory treatment in patients with dry eye.

PURPOSE: This study characterized conjunctival microvascular morphological and haemodynamic responses after anti-inflammatory treatment in dry eye (DE). MATERIALS AND METHODS: Twenty-five patients with moderate DE (17 females and 8 males aged 48 ± 16 years) who underwent anti-inflammatory therapy (0.1% fluorometholone) and 25 healthy subjects (20 females and 5 males aged 48 ± 17 years) recruited as controls were enrolled. The conjunctival blood flow rate (BFR), blood flow velocity (BFV) and vessel diameter were measured by functional slit-lamp biomicroscopy (FSLB). DE symptoms and signs were assessed. All measurements were performed at baseline and at 30 and 60 days after commencement of treatment. RESULTS: At baseline, the conjunctival BFR, BFV, and vessel diameter were higher in the DE group than in the control group (p < 0.05). The BFR, BFV and corneal fluorescein staining (CFS) scores decreased at 60 days after therapy compared to at baseline and 30 days (all pcorrected < 0.05); Ocular surface diseases index (OSDI), the hyperaemia index (HI) and vessel diameters only showed significant decreases at 30 days. Moreover, significant increases in the noninvasive tear film break-up time (NI-BUT) and Schirmer I test score (ST) were observed. The CFS score correlated positively with BFV (r = 0.46), BFR (r = 0.58) and vessel diameter (r = 0.47). CONCLUSION: This study characterized conjunctival microvascular responses to anti-inflammatory treatment in DE patients. The results suggest that conjunctival BFV and BFR can be used as dynamic markers for treatment efficacy in DE.

Accuracy of intraocular lens power calculations in paediatric eyes.

IMPORTANCE: There is no clear consensus on which intraocular lens (IOL) power calculation formula provides the best refractive prediction in the paediatric population. BACKGROUND: To evaluate the predictability of desired postoperative refractive outcomes by using six IOL formulas in paediatric cataract cases. DESIGN: Retrospective case series. PARTICIPANTS: A total of 377 eyes in 377 paediatric patients (<13 years of age) who received primary IOL implants in the capsular bag. METHODS: This study utilized formulas, namely, SRK II, SRK/T, Hoffer Q, Holladay 1, T2 and Super formula. Prediction errors were calculated based on the difference between the postoperative refraction and the refraction predicted by each formula. MAIN OUTCOME MEASURES: The mean prediction error, mean absolute error, median absolute error, percentages of eyes within the prediction errors of ±0.50 D, ±1.00 D and ± 2.00 D. RESULTS: The mean axial length was 22.48 ± 1.91 mm (<22.0 mm for 161 eyes). The average age at surgery was 55.21 ± 28.01 months (<24 months for 37 eyes). The mean prediction error was positive (hyperopic error) with all formulas. Compared to the other IOL power formulas, SRK II showed significantly higher absolute errors (P < .001). Hoffer Q and Holladay 1 generated the least absolute error, followed closely by Super formula. Multiple logistic analyses indicated that age at time of surgery was an independent factor significantly contributing to the refractive surprise using all formulas. CONCLUSIONS AND RELEVANCE: SRK II was the least predictable formula in this study. HofferQ and Holladay 1 yielded the best predictive values.

Biochemical characterization of G64W mutant of acidic beta-crystallin 4.

Crystallins are structural proteins in the lens that last a lifetime with little turnover. Deviant in crystallins can cause rare but severe visual impairment, namely, congenital cataracts. It is reported that several mutations in the acidic ß-crystallin 4 (CRYBA4) are related to congenital cataracts. However, the pathogenesis of these mutants is not well understood at molecular level. Here we evaluate the biochemical properties of wild type CRYBA4 (CRYBA4WT) and a pathogenic G64W mutant (CRYBA4G64W) including protein folding, polymerization state and protein stability. Furthermore, we explore the differences in their interactions with α-crystallin A (CRYAA) and basic ß-crystallin 1 (CRYBB1) via yeast two-hybrid and pull-down assay in vitro, through which we find that G64W mutation leads to protein misfolding, decreases protein stability, blocks its interaction with CRYBB1 but maintains its interaction with CRYAA. Our results deepen our understanding of the pathogenesis of congenital cataracts.

IL-4/IL-13 Signaling Inhibits the Potential of Early Thymic Progenitors To Commit to the T Cell Lineage.

Early thymic progenitors (ETPs) are endowed with diverse potencies and can give rise to myeloid and lymphoid lineage progenitors. How the thymic environment guides ETP commitment and maturation toward a specific lineage remains obscure. We have previously shown that ETPs expressing the heteroreceptor (HR) comprising IL-4Rα and IL-13Rα1 give rise to myeloid cells but not T cells. In this article, we show that signaling through the HR inhibits ETP maturation to the T cell lineage but enacts commitment toward the myeloid cells. Indeed, HR+ ETPs, but not HR- ETPs, exhibit activated STAT6 transcription factor, which parallels with downregulation of Notch1, a critical factor for T cell development. Meanwhile, the myeloid-specific transcription factor C/EBPα, usually under the control of Notch1, is upregulated. Furthermore, in vivo inhibition of STAT6 phosphorylation restores Notch1 expression in HR+ ETPs, which regain T lineage potential. In addition, upon stimulation with IL-4 or IL-13, HR- ETPs expressing virally transduced HR also exhibit STAT6 phosphorylation and downregulation of Notch1, leading to inhibition of lymphoid, but not myeloid, lineage potential. These observations indicate that environmental cytokines play a role in conditioning ETP lineage choice, which would impact T cell development.

On the Role IL-4/IL-13 Heteroreceptor Plays in Regulation of Type 1 Diabetes.

Type 1 diabetes (T1D) manifests when the insulin-producing pancreatic ß cells are destroyed as a consequence of an inflammatory process initiated by lymphocytes of the immune system. The NOD mouse develops T1D spontaneously and serves as an animal model for human T1D. The IL-4Rα/IL-13Rα1 heteroreceptor (HR) serves both IL-4 and IL-13 cytokines, which are believed to function as anti-inflammatory cytokines in T1D. However, whether the HR provides a responsive element to environmental (i.e., physiologic) IL-4/IL-13 in the regulation of peripheral tolerance and the development of T1D has yet to be defined. In this study, NOD mice deficient for the HR have been generated by means of IL-13Rα1 gene disruption and used to determine whether such deficiency affects the development of T1D. Surprisingly, the findings indicate that NOD mice lacking the HR (13R-/-) display resistance to T1D as the rise in blood glucose level and islet inflammation were significantly delayed in these HR-deficient relative to HR-sufficient (13R+/+) mice. In fact, the frequency and spleen-to-pancreas dynamics of both Th1 and Th17 cells were affected in 13R-/- mice. This is likely due to an increase in the frequency of mTGFß+Foxp3int regulatory T cells and the persistence of CD206+ macrophages in the pancreas as both types of cells confer resistance to T1D upon transfer to 13R+/+ mice. These findings reveal new insights as to the role environmental IL-4/IL-13 and the HR play in peripheral tolerance and the development of T1D.

F0-induced formant measurement errors result in biased variabilities.

Many developmental studies attribute reduction of acoustic variability to increasing motor control. However, linear prediction-based formant measurements are known to be biased toward the nearest harmonic of F0, especially at high F0s. Thus, the amount of reported formant variability generated by changes in F0 is unknown. Here, 470 000 vowels were synthesized, mimicking statistics reported in four developmental studies, to estimate the proportion of formant variability that can be attributed to F0 bias, as well as other formant measurement errors. Results showed that the F0-induced formant measurements errors are large and systematic, and cannot be eliminated by a large sample size.

Long non-coding RNA T-cell leukemia/lymphoma 6 serves as a sponge for miR-21 modulating the cell proliferation of retinoblastoma through PTEN.

Retinoblastoma (Rb) is one of the most common eye malignancies occur in childhood. The crucial roles of non-coding RNAs, particularly long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been widely reported in Rb progression. In the present study, we found the expression of lncRNA T-cell leukemia/lymphoma 6 (TCL6) was significantly downregulated in Rb tissues and cell lines. Knockdown of lncRNA TCL6 promoted cell proliferation while reduced cell apoptosis in Rb cells. Moreover, lncRNA TCL6 serves as a sponge for miR-21, a previously-reported oncogenic miRNA in Rb, by direct targeting to negatively regulated miR-21 expression, therefore modulating Rb proliferation through miR-21. TCL6 overexpression inhibited Rb cell proliferation while miR-21 overexpression exerted an opposing effect; the effect of TCL6 overexpression was partially attenuated by miR-21 overexpression. PTEN/PI3K/AKT signaling pathway was involved in lncRNA TCL6/miR-21 axis modulating Rb cell proliferation. Taken together, lncRNA TCL6 serves as a tumor suppressor by acting as a sponge for miR-21 to counteract miR-21-mediated PTEN repression.

Preoperative profile of inflammatory factors in aqueous humor correlates with postoperative inflammatory response in patients with congenital cataract.

Purpose: To measure the aqueous humor concentrations of inflammatory factors in patients with congenital cataract and to investigate the relationship between the levels and postoperative inflammatory responses. Methods: Aqueous humor samples were prospectively collected from 65 eyes of children with congenital cataracts from January to June 2015. The levels of 41 inflammation-related cytokines, chemokines, and growth factors in aqueous humor were measured using multiplex bead immunoassay. Data on patient demographics and postoperative inflammatory response evaluation of posterior capsule opacification (EPCO) scores were collected for correlation analysis of short- and long-term postoperative inflammatory responses, respectively. Results: Fifteen inflammatory factors were differentially expressed between congenital cataract and age-related cataract. EGF and IL-3 were positively correlated, whereas IL-8 and MCP-1 were negatively correlated with age. TNFα, IL-17A, IL-3, and sCD40L were preferably expressed in specific morphological types of congenital cataract. One month and 3 months postoperatively, PDGF-AA exhibited a positive correlation with the EPCO scores, whereas IL-1RA exhibited a negative correlation. Macrophage-derived chemokine (MDC) showed a positive correlation with the EPCO scores 1 year postoperatively. Conclusions: This study provided a comprehensive preoperative profile of inflammatory factors and their correlations with postoperative inflammatory responses in patients with congenital cataract. These factors may serve as potential biomarkers to predict the postoperative inflammatory response. These findings will also facilitate the development of anti-inflammatory medications in the perioperative period.

Antigen-Specific Immune Modulation Targets mTORC1 Function To Drive Chemokine Receptor-Mediated T Cell Tolerance.

To contain autoimmunity, pathogenic T cells must be eliminated or diverted from reaching the target organ. Recently, we defined a novel form of T cell tolerance whereby treatment with Ag downregulates expression of the chemokine receptor CXCR3 and prevents diabetogenic Th1 cells from reaching the pancreas, leading to suppression of type 1 diabetes (T1D). This report defines the signaling events underlying Ag-induced chemokine receptor-mediated tolerance. Specifically, we show that the mammalian target of rapamycin complex 1 (mTORC1) is a major target for induction of CXCR3 downregulation and crippling of Th1 cells. Indeed, Ag administration induces upregulation of programmed death-ligand 1 on dendritic cells in a T cell-dependent manner. In return, programmed death-ligand 1 interacts with the constitutively expressed programmed death-1 on the target T cells and stimulates docking of Src homology 2 domain-containing tyrosine phosphatase 2 phosphatase to the cytoplasmic tail of programmed death-1. Active Src homology 2 domain-containing tyrosine phosphatase 2 impairs the signaling function of the PI3K/protein kinase B (AKT) pathway, leading to functional defect of mTORC1, downregulation of CXCR3 expression, and suppression of T1D. Thus, mTORC1 component of the metabolic pathway serves as a target for chemokine receptor-mediated T cell tolerance and suppression of T1D.