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SummaryPersistent systemic inflammation in persons with HIV (PWH) is accompanied by an increased risk of metabolic disease. Yet, changes in the innate and adaptive immune system in PWH who develop metabolic disease remain poorly defined. Using unbiased approaches, we show that PWH with prediabetes/diabetes have a significantly higher proportion of circulating CD14+monocytes complexed to T cells. The complexed CD3+T cells and CD14+monocytes demonstrate functional immune synapses, increased expression of proinflammatory cytokines, and greater glucose utilization. Furthermore, these complexes harbor more latent HIV DNA compared to CD14+monocytes or CD4+T cells. Our results demonstrate that circulating CD3+CD14+T cell-monocyte pairs represent functional dynamic cellular interactions that likely contribute to inflammation and, in light of their increased proportion, may have a role in metabolic disease pathogenesis. These findings provide an incentive for future studies to investigate T cell-monocyte immune complexes as mechanistic in HIV cure and diseases of aging.Graphical AbstractHighlightsPersons with HIV and diabetes have increased circulating CD3+CD14+T cell-monocyte complexes.CD3+CD14+T cell-monocytes are a heterogenous group of functional and dynamic complexes.We can detect HIV in T cell-monocyte complexes.The proportion of CD3+CD14+T cell-monocyte complexes is positively associated with blood glucose levels and negatively with plasma IL-10 and CD4+T regulatory cells.

SUMMARYRNA-based vaccines against SARS-CoV-2 are critical to limiting COVID-19 severity and spread. Cellular mechanisms driving antigen-specific responses to these vaccines, however, remain uncertain. We used single-cell technologies to identify and characterized antigen-specific cells and antibody responses to the RNA vaccine BNT162b2 in longitudinal samples from a cohort of healthy donors. Mass cytometry and machine learning pinpointed a novel expanding, population of antigen-specific non-canonical memory CD4+ and CD8+ T cells. B cell sequencing suggested progression from IgM, with apparent cross-reactivity to endemic coronaviruses, to SARS-CoV-2-specific IgA and IgG memory B cells and plasmablasts. Responding lymphocyte populations correlated with eventual SARS-CoV-2 IgG and a donor lacking these cell populations failed to sustain SARS-CoV-2-specific antibodies and experienced breakthrough infection. These integrated proteomic and genomic platforms reveal an antigen-specific cellular basis of RNA vaccine-based immunity.ONE SENTENCE SUMMARYSingle-cell profiling reveals the cellular basis of the antigen-specific response to the BNT162b2 SARS-CoV-2 RNA vaccine.

ObjectivesThe idiopathic inflammatory myopathies (IIM) are a clinically heterogeneous group of conditions affecting the skin, muscle, joint, and lung in various combinations. This study aims to investigate the immunologic heterogeneity through detailed immunophenotyping of peripheral blood mononuclear cells (PBMCs) in IIM patients and healthy controls.MethodsWe collected PBMCs from 17 patients with a clinical diagnosis of inflammatory myositis in the inpatient or outpatient setting and performed immunophenotyping using mass cytometry by time of flight (CyTOF) to simultaneously characterize B, T, and myeloid cell subsets. Data were analyzed using a combination of supervised biaxial gating and unsupervised clustering algorithms including t-distributed stochastic neighbor embedding (tSNE), cluster identification, characterization, and regression (CITRUS), and marker enrichment modeling (MEM).ResultsWe identified two distinct immune signatures amongst IIM patients. In one signature, increased CD19+CXCR4hiCCR7hi cells correlated with increased CD3+CXCR4hiCD38hi (r=0.62, p=0.009) and CD14+CD16-CXCR4+CD38+HLADR-(r=0.61, p=0.01) populations. In the second signature, increased CD19+CD21loCD11c+ cells correlated with an increased CD3+CD4+PD1+ (r=0.60, p=0.01) population. Other shared immunologic features amongst IIM patients compared to healthy controls included decreased surface expression of RP105/CD180 on B cells (median mass intensity 39.9 ± 16.0 v. 60.9 ± 20.1, p=0.002). In the T cell compartment, all circulating CD3+CXCR3+ subsets (2.7 ± 2.4 v. 9.6 ± 8.1% of all PBMCs, p=0.0004) were reduced.ConclusionBased on circulating B cell phenotype, we identified two distinct immunologic signatures in IIM patients. Future work is needed to determine the significance of these immune signatures for clinical manifestations and treatment responses.