Temporal dynamics and genomic programming of plasma cell fates.

Affinity-matured plasma cells (PCs) of varying lifespans are generated through a germinal center (GC) response. The developmental dynamics and genomic programs of antigen-specific PC precursors remain to be elucidated. Here, using a model antigen in mice, we demonstrate biphasic generation of PC precursors, with those generating long-lived bone marrow PCs preferentially produced in the late phase of GC response. Clonal tracing using single-cell RNA sequencing and B cell antigen receptor sequencing in spleen and bone marrow compartments, coupled with adoptive transfer experiments, reveals a new PC transition state that gives rise to functionally competent PC precursors. The latter undergo clonal expansion, dependent on inducible expression of TIGIT. We propose a model for the proliferation and programming of precursors of long-lived PCs, based on extended antigen encounters in the GC.

Sliding Window INteraction Grammar (SWING): a generalized interaction language model for peptide and protein interactions.

The explosion of sequence data has allowed the rapid growth of protein language models (pLMs). pLMs have now been employed in many frameworks including variant-effect and peptide-specificity prediction. Traditionally, for protein-protein or peptide-protein interactions (PPIs), corresponding sequences are either co-embedded followed by post-hoc integration or the sequences are concatenated prior to embedding. Interestingly, no method utilizes a language representation of the interaction itself. We developed an interaction LM (iLM), which uses a novel language to represent interactions between protein/peptide sequences. Sliding Window Interaction Grammar (SWING) leverages differences in amino acid properties to generate an interaction vocabulary. This vocabulary is the input into a LM followed by a supervised prediction step where the LM's representations are used as features. SWING was first applied to predicting peptide:MHC (pMHC) interactions. SWING was not only successful at generating Class I and Class II models that have comparable prediction to state-of-the-art approaches, but the unique Mixed Class model was also successful at jointly predicting both classes. Further, the SWING model trained only on Class I alleles was predictive for Class II, a complex prediction task not attempted by any existing approach. For de novo data, using only Class I or Class II data, SWING also accurately predicted Class II pMHC interactions in murine models of SLE (MRL/lpr model) and T1D (NOD model), that were validated experimentally. To further evaluate SWING's generalizability, we tested its ability to predict the disruption of specific protein-protein interactions by missense mutations. Although modern methods like AlphaMissense and ESM1b can predict interfaces and variant effects/pathogenicity per mutation, they are unable to predict interaction-specific disruptions. SWING was successful at accurately predicting the impact of both Mendelian mutations and population variants on PPIs. This is the first generalizable approach that can accurately predict interaction-specific disruptions by missense mutations with only sequence information. Overall, SWING is a first-in-class generalizable zero-shot iLM that learns the language of PPIs.

SARS-CoV-2 mRNA Vaccines Induce Greater Complement Activation and Decreased Viremia and Nef Antibodies in Men With HIV-1.

BACKGROUND: Immune dysregulation in people with human immunodeficiency virus-1 (PWH) persists despite potent antiretroviral therapy and, consequently, PWH tend to have lower immune responses to licensed vaccines. However, limited information is available about the impact of mRNA vaccines in PWH. This study details the immunologic responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in PWH and their impact on HIV-1. METHODS: We quantified anti-S immunoglobulin G (IgG) binding and neutralization of 3 SARS-CoV-2 variants of concern and complement activation in blood from virally suppressed men with HIV-1 (MWH) and men without HIV-1 (MWOH), and the characteristics that may impact the vaccine immune responses. We also studied antibody levels against HIV-1 proteins and HIV-1 plasma RNA. RESULTS: MWH had lower anti-S IgG binding and neutralizing antibodies against the 3 variants compared to MWOH. MWH also produced anti-S1 antibodies with a 10-fold greater ability to activate complement and exhibited higher C3a blood levels than MWOH. MWH had decreased residual HIV-1 plasma viremia and anti-Nef IgG approximately 100 days after immunization. CONCLUSIONS: MWH respond to SARS-CoV-2 mRNA vaccines with lower antibody titers and with greater activation of complement, while exhibiting a decrease in HIV-1 viremia and anti-Nef antibodies. These results suggest an important role of complement activation mediating protection in MWH.

From bench to bedside via bytes: Multi-omic immunoprofiling and integration using machine learning and network approaches.

A significant surge in research endeavors leverages the vast potential of high-throughput omic technology platforms for broad profiling of biological responses to vaccines and cutting-edge immunotherapies and stem-cell therapies under development. These profiles capture different aspects of core regulatory and functional processes at different scales of resolution from molecular and cellular to organismal. Systems approaches capture the complex and intricate interplay between these layers and scales. Here, we summarize experimental data modalities, for characterizing the genome, epigenome, transcriptome, proteome, metabolome, and antibody-ome, that enable us to generate large-scale immune profiles. We also discuss machine learning and network approaches that are commonly used to analyze and integrate these modalities, to gain insights into correlates and mechanisms of natural and vaccine-mediated immunity as well as therapy-induced immunomodulation.

Temporal dynamics and genomic programming of plasma cell fates.

Affinity-matured plasma cells (PCs) of varying lifespans are generated through a germinal center (GC) response. The developmental dynamics and genomic programs of antigen-specific PC precursors remain to be elucidated. Using a model antigen, we demonstrate biphasic generation of PC precursors, with those generating long-lived bone marrow PCs preferentially produced in the late phase of GC response. Clonal tracing using scRNA-seq+BCR-seq in spleen and bone marrow compartments, coupled with adoptive transfer experiments, reveal a novel PC transition state that gives rise to functionally competent PC precursors. The latter undergo clonal expansion, dependent on inducible expression of TIGIT. We propose a model for the proliferation and programming of precursors of long-lived PCs, based on extended antigen encounters followed by reduced antigen availability.