Biology subjects

Brooks, D. G.

Publications and source records attributed to Brooks, D. G..

4 recordsLinked to original sources

bioRxiv2026

High Dimensional Immune Profiling Reveals CD39 as a Correlate of Tuberculosis Disease Severity

Immune biomarkers of tuberculosis (TB) disease severity present a challenging area of research that remains poorly understood. New technologies are able to perform larger, unbiased studies that can unravel the complex host-pathogen dynamics occurring during a Mycobacterium tuberculosis infection, the causative agent of TB. In this study, we designed a high dimensional approach combining viable bacterial burden (CFU, colony forming units) with time-of-flight mass cytometry (CyTOF) analysis to profile differences in cell-type abundance and cell-type specific protein expression during states of low, intermediate and high TB disease burden. Broadly, we segregated cell-type specific immune responses into those driven by bacterial burden and/or the mycobacterial infection strain. Interrogating these immune signatures allowed us to identify ATP-catabolizing protein CD39 as a correlate of disease severity. Treatment of mice with a small molecule inhibitor of CD39 promoted effector T cell functions and CD4 T cell expansion during Mtb infection. Collectively, our data defines the differential lung immune environment between various mycobacterial disease severity states and uncovers a potential immune biomarker of infection and therapeutic immunomodulating target to aid in the treatment of TB.

immunology↗

bioRxiv2026

Sequential infection reprograms the immune landscape to shape future responses

Mouse models have been instrumental in defining immune mechanisms but often fail to capture the complexity of human immunity, limiting clinical translation. A major limitation is the immunological immaturity of specific pathogen-free (SPF) mice relative to pathogen-experienced adult humans. Here, we use a sequential infection (SI) model that recapitulates cumulative pathogen exposure and define its impact on immune composition and function. Beyond the previously reported expansion of memory T cells, SI induced durable, system-wide remodeling across lymphoid and non-lymphoid tissues, reshaping innate and adaptive immune populations, tissue-resident immunity, and hematopoietic output. Single-cell transcriptomic analyses revealed inflammatory imprinting of naive CD4 and CD8 T cells, whereas memory T cells acquired enhanced effector programs coupled with reduced biosynthetic activity, transcriptional states that more closely resemble those of pathogen-experienced adult humans. Functionally, SI mice recapitulated the human response to anti-CD28 super-agonist and exhibited altered magnitude and differentiation of acute and chronic antiviral T cell responses, demonstrating that cumulative pathogen exposure reshapes both existing immunity and the generation of future immune responses. Thus, cumulative pathogen exposure coordinately remodels hematopoiesis and naive and memory lymphocyte states, establishing a durable inflammation-experienced immune landscape that reshapes both immune memory and future immune responses, with broad implications for the translational fidelity of preclinical mouse models.

immunology↗

bioRxiv2026

Functional Type I and Type II interferon crosstalk restricts progenitor exhausted CD8 T cells through spatial exclusion and checkpoint enforcement

Type I interferon (IFN-I) and interferon-{gamma} (IFN{gamma}) are central regulators of antiviral immunity, yet how they cooperatively govern CD8 T cell fate during chronic infection remains unresolved. Here, we uncover a previously unrecognized, spatially encoded interferon circuit that actively constrains progenitor exhausted CD8 T cells (Tpex) during chronic LCMV infection. Persistent IFN-I signaling indirectly restricts Tpex expansion by enforcing their sequestration within PDL1-rich B cell niches of lymphoid tissue and by suppressing T cell-derived IFN{gamma}. Blockade of IFN-I signaling enables Tpex migration into T cell zones of splenic follicles driving IFN{gamma} production, which in turn sustains PDL1 expression on myeloid cells to re-impose local inhibitory pressure. Combined IFN-I and IFN{gamma} blockade disrupts this feedback, promoting coordinated niche redistribution of Tpex and checkpoint remodeling that drives robust Tpex expansion. Single-cell transcriptomics reveal that this layered IFN-I-IFN{gamma} interplay establishes a regulatory balance that constrains Tpex proliferation while preserving effector-like transcriptional programs in their progeny effector CD8 T cells, ultimately preventing premature terminal differentiation. Thus, interferons orchestrate the coordinated T cell-myeloid regulatory circuit that integrates tissue organization, cytokine feedback, and checkpoint control to regulate CD8 T cell exhaustion during chronic infection.

immunology↗

bioRxiv2024

A Unified Atlas of T cell Glycophysiology

Glycans are emerging as important regulators of T cell function but remain poorly characterized across the functionally distinct populations that exist in vivo. Here, we couple single-cell analysis technologies with soluble lectins and chemical probes to interrogate glycosylation patterns on major T cell populations across multiple mouse and human tissues. Our analysis focused on terminal glycan epitopes with immunomodulatory functions, including sialoglycan ligands for Siglecs. We demonstrate that glycosylation patterns are diverse across the resting murine T cell repertoire and dynamically remodelled in response to antigen-specific stimulation. Surprisingly, we find that human T cell populations do not share the same glycoprofiles or glycan remodelling dynamics as their murine counterparts. We show that these differences can be explained by divergent regulation of glycan biosynthesis pathways between the species. These results highlight fundamental glycophysiological differences between mouse and human T cells and reveal features that are critical to consider for glycan-targeted therapies.

immunology↗