Unprimed mice harbor a substantial population of "memory-phenotype" CD8 + T cells (CD8-MP cells) that exhibit hallmarks of activation and innate-like functional properties. Due to the lack of faithful markers to distinguish CD8-MP cells from bona fide CD8 + memory T cells, the developmental origins and antigen specificities of CD8-MP cells remain incompletely defined. Using deep T cell antigen receptor (TCR) sequencing, we found that the TCRs expressed by CD8-MP cells are highly recurrent and distinct from the TCRs expressed by naive-phenotype CD8 + T cells. CD8-MP clones exhibited reactivity to widely expressed self-ligands. T cell precursors expressing CD8-MP TCRs upregulated the transcription factor Eomes during maturation in the thymus, prior to induction of the full memory phenotype, suggestive of a unique program triggered by recognition of self-ligands. Moreover, CD8-MP cells infiltrate oncogene-driven prostate tumors and express high densities of PD-1, suggesting a potential role in anti-tumor immunity and response to immunotherapy.

Objective To derive and validate a new ecological measure of the social determinants of health (SDoH), calculable at the zip code or county level. Data Sources and Study Setting The most recent releases of secondary, publicly available data were collected from national U.S. health agencies as well as state and city public health departments. Study Design The Social Vulnerability Metric (SVM) was constructed from U.S. zip‐code level measures (2018) from survey data using multidimensional Item Response Theory and validated using outcomes including all‐cause mortality (2016), COVID‐19 vaccination (2021), and emergency department visits for asthma (2018). The SVM was also compared with the existing Centers for Disease Control and Prevention's Social Vulnerability Index (SVI) to determine convergent validity and differential predictive validity. Data Collection/Extraction Methods The data were collected directly from published files available to the public online from national U.S. health agencies as well as state and city public health departments. Principal Findings The correlation between SVM scores and national age‐adjusted county all‐cause mortality was r = 0.68. This correlation demonstrated the SVM's robust validity and outperformed the SVI with an almost four‐fold increase in explained variance (46% vs. 12%). The SVM was also highly correlated (r ≥ 0.60) to zip‐code level health outcomes for the state of California and city of Chicago. Conclusions The SVM offers a measurement tool improving upon the performance of existing SDoH composite measures and has broad applicability to public health that may help in directing future policies and interventions. The SVM provides a single measure of SDoH that better quantifies associations with health outcomes.

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IMPORTANCE There has been large geographic inequity in vaccination coverage across Chicago, Illinois, with higher vaccination rates in zip codes with residents who predominantly have high incomes and are White. OBJECTIVE To determine the association between inequitable zip code-level vaccination coverageand COVID-19 mortality in Chicago.

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Background. In the United States, over half of pediatric candidates receive exceptions and status upgrades that increase their allocation model of end-stage liver disease/pediatric end-stage liver disease (MELD/PELD) score above their laboratory MELD/PELD score. We determined whether these “nonstandardized” MELD/PELD exceptions accurately depict true pretransplant mortality risk. Methods. Using data from the Scientific Registry of Transplant Recipients, we identified pediatric candidates (<18 y of age) with chronic liver failure added to the waitlist between June 2016 and September 2021 and estimated all-cause pretransplant mortality with mixed-effects Cox proportional hazards models that treated allocation MELD/PELD and exception status as time-dependent covariates. We also estimated concordance statistics comparing the performance of laboratory MELD/PELD with allocation MELD/PELD. We then compared the proportion of candidates with exceptions before and after the establishment of the National Liver Review Board. Results. Out of 2026 pediatric candidates listed during our study period, 403 (19.9%) received an exception within a week of listing and 1182 (58.3%) received an exception before delisting. Candidates prioritized by their laboratory MELD/PELD scores had an almost 9 times greater risk of pretransplant mortality compared with candidates who received the same allocation score from an exception (hazard ratio 8.69; 95% confidence interval, 4.71-16.03; P < 0.001). The laboratory MELD/PELD score without exceptions was more accurate than the allocation MELD/PELD score with exceptions (Harrell’s c-index 0.843 versus 0.763). The proportion of patients with an active exception at the time of transplant decreased significantly after the National Liver Review Board was implemented (67.4% versus 43.4%, P < 0.001). Conclusions. Nonstandardized exceptions undermine the rank ordering of pediatric candidates with chronic liver failure.

Tissue stem cells are hierarchically organized. Those that are most primitive serve as key drivers of regenerative response but the signals that selectively preserve their functional integrity are largely unknown. Here, we identify a secreted factor, Semaphorin 4A (Sema4A), as a specific regulator of myeloid-biased hematopoietic stem cells (myHSC), which are positioned at the top of the HSC hierarchy. Lack of Sema4A leads to exaggerated myHSC (but not downstream balanced HSC) proliferation after acute inflammatory stress, indicating that Sema4A enforces myHSC quiescence. Strikingly, aged Sema4A knock-out myHSC expand but almost completely lose reconstitution capacity. The effect of Sema4A is non cell-autonomous, since upon transplantation into Sema4A-deficient environment, wild-type myHSC excessively proliferate but fail to engraft long-term. Sema4A constrains inflammatory signaling in myHSC and acts via a surface receptor Plexin-D1. Our data support a model whereby the most primitive tissue stem cells critically rely on a dedicated signal from the niche for self-renewal and life-long persistence.

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