Biology subjects

Merkenschlager, J.

Publications and source records attributed to Merkenschlager, J..

5 recordsLinked to original sources

bioRxiv2026

immgenT CD4: a reference landscape of mouse CD4+ T cell

CD4+ T cells are orchestrators of the immune system with diverse effector functions. Their full molecular diversity remains unclear due to the lack of a unified framework. Within the immgenT project, we profiled RNA, surface markers, and TCR clonotypes in conventional CD4+ T cells across >700 samples. Integration with a joint RNA-protein deep generative model revealed an ensemble of 20 CD4 states that account for all cells across tissues and challenges. Small, highly polarized clusters ("tips") that evoke Th1, Th2, Th17, and Tfh states co-exist with a majority of activated cells with mixed programs occupying "midland" states. Unlike CD8+ T cells, memory CD4+ cells largely mapped to the same states as effectors. Resting states proved quite diverse, and we uncovered unexpected similarities between Tfh and chronically stimulated states. Together, immgenT provides a unified molecular reference for CD4+ T cell diversity.

immunology↗

bioRxiv2026

Fc receptor dependent and independent mechanisms of antibody-mediatedenhancement of immune responses

Immune memory responses are rapid and qualitatively distinct from primary responses. They typically develop in the presence of antigen-experienced memory T and B cells and pre-existing antibodies. Although the contribution of T and B cells to recall responses is well defined, the contribution of antibody "memory" and the mechanisms by which pre-existing antibodies modulate the development of germinal center and plasma cell responses is not precisely understood. Here we report on mechanisms that mediate antibody enhancement of germinal center (GC) and plasmablast (PB) compartments, and the parallel process by which they change the affinity threshold for B cell recruitment into immune responses. The data indicate that antibody-mediated enhancement of GC and PB responses is Fc gamma receptor (Fc{gamma}R) dependent and largely complement receptor 1 and 2 (CR1/2) independent. In contrast, the reduction in the affinity threshold for GC entry is independent of both Fc{gamma}Rs and CR1/2. SummaryCipolla et al. show that antibody can modulate immune responses via both Fc gamma receptor dependent and independent mechanisms. These mechanisms influence both the magnitude and composition of the germinal center response.

immunology↗

bioRxiv2026

immgenT: A Comprehensive Reference of Convergent T-cell States in the Mouse

The immgenT collaborative project generated a comprehensive molecular atlas of T cells spanning virtually all mouse organs and disease states, profiling ~800,000 cells from 750 samples with RNA, 128-plex surface protein, and {beta}TCR sequence. Applying a deep generative model to joint RNA and protein data defined the landscape of T-cell states organized into eight lineages and 107 robust clusters, integrating similar cells from different contexts, and resolving prior nomenclatures. Analysis of effector molecules, transcription factors and modules showed that both immunological functions and regulatory programs are shared across cell states. This framework provides a stable, reusable reference, demonstrated by computationally integrating 16 external datasets from diverse biological contexts. A set of public web tools supports browsing of these data and mapping of any dataset onto the immgenT framework. These results propose a molecular classification of T cells organized around a set of shared states reused across immunological contexts.

immunology↗

bioRxiv2025

Modeling the Synergetic Dynamics of B cells and TFH cells in Germinal Center Reactions

B cells producing high-affinity antibodies arise through affinity maturation within germinal centers (GCs), where selection is driven by T follicular helper (TFH) cells. Recent studies have shown that, like GC B cells, TFH cells also undergo antigen-dependent selection, with competition among TFH clones dictated by their ability to recognize and stimulate B cells. This sensitivity-dependent selection process leads to dynamic remodeling of the TFH repertoire over time. Despite the essential role of TFH cells in B cell selection, the functional consequences of the time evolution of the TFH cell population remains poorly understood. To address this gap, we developed a population dynamics model that explicitly incorporates key TFH cell properties and dynamics. Our analysis predicts that dynamic feedback between B and TFH cell populations provides robust homeostatic regulation of their numbers in the GC, yielding a stable lymphocyte ratio that we verify experimentally. Moreover, our model predicts that TFH clone sensitivity dictates distinct evolutionary strategies during affinity maturation, with low-sensitivity TFH cells accelerating affinity gain at the expense of B cell diversity, while high-sensitivity TFH cells slow affinity maturation but preserve a broader B cell repertoire. These findings highlight the importance of co-regulation between TFH and B cells and suggest that reciprocal stimulation allows the immune system to tune the tradeoff between the speed of affinity gain and the breadth of B cell diversity--a principle that may extend to other adaptive systems. Significance StatementEffector B cells that secrete high-affinity antibodies and form immunological memory are essential for humoral immunity and arise from germinal center (GC) reactions. Within GCs, B cells undergo an accelerated version of Darwinian evolution to enhance antibody affinity. This process is orchestrated by T follicular helper (TFH) cells which provide stimulatory signals to selected B cells and undergo their own antigen-driven selection. To investigate this co-evolutionary process, we developed a tractable population-level model of the GC reaction. Our analysis reveals that the reciprocal stimulation of B and TFH cells provides a robust mechanism for regulating the B:TFH ratio and tuning the tradeoff between the speed of affinity maturation and the diversity of the antibody response.

immunology↗

bioRxiv2024

Affinity maturation of antibody responses is mediated by differential plasma cell proliferation

Increased antibody affinity over time after vaccination, known as affinity maturation, is a prototypical feature of immune responses. Recent studies have shown that a diverse collection of B cells, producing antibodies with a wide spectrum of different affinities, are selected into the plasma cell (PC) pathway. How affinity-permissive selection enables PC affinity maturation remains unknown. Here we report that PC precursors (prePC) expressing high affinity antibodies receive higher levels of T follicular helper (Tfh)-derived help and divide at higher rates than their lower affinity counterparts once they leave the GC. Thus, differential cell division by selected prePCs accounts for how diverse precursors develop into a PC compartment that mediates serological affinity maturation.

immunology↗