Biology subjects

Yates, A. J.

Publications and source records attributed to Yates, A. J..

7 recordsLinked to original sources

bioRxiv2026

Beyond the blood: Tissue-resident immunity shapes SARS-CoV-2 vaccine antibody responses

Infections and vaccinations elicit coordinated humoral and cellular adaptive immune responses that together provide protection. In addition to antibodies, pathogen-specific memory T and Bcells persist in blood and tissues, but it remains unclear how their composition and spatial distribution relate to serum antibody titers, the most common correlate of vaccine-induced protection. Understanding these relationships is essential for predicting vaccine efficacy and optimizing immunization strategies. We analyzed tissues from 58 adult human organ donors vaccinated against SARS-CoV-2, including individuals with and without prior infection. Using multivariate imputation, dimensionality reduction, and correlation, regression, and causal analyses, we identified immune signatures linking memory B cell, CD4 T cell, and CD8 T cell subsets in spleen, lung, and lung-draining lymph nodes with antibody titers and neutralizing activity. Our analyses indicate that humoral immunity is driven primarily by virus-specific B cellsand CD4 T cells in lymphoid tissues rather than blood, whereas tissue-localized CD8 T cell responses, although correlated with antibody levels, develop independently. These findings demonstrate that cross-sectional immune profiling across multiple tissues recapitulates established immunological principles and reveal that serum antibody responses emerge from coordinated cellular immune responses distributed throughout the body.

immunology↗

bioRxiv2026

Quorum sensing underlies the establishment and maintenance of marginal zone B cells

The marginal zone (MZ) of the spleen harbors B cells that play an indispensable role in immune defense, orchestrating rapid responses to bloodborne pathogens. Under steady-state conditions, MZ B cell numbers are maintained through the balance of de novo generation from precursors, proliferative self-renewal, and loss. The mechanisms governing this homeostatic control remain elusive. Further, the developmental pathways underlying the establishment and continued supplementation of the MZ B cell compartment are not fullyelucidated. To address these gaps, we combined multiple fate-mapping tools and mathematical models to study MZ B cell dynamics in mice across the life course. Our analyses find evidence of quorum sensing mechanisms that regulate both the accumulation of mature MZ B cells during early life and their maintenance throughout adulthood. Specifically, we demonstrate that they derive predominantly from transitional B cell precursors with an efficiency that increases with age, reaching stable levels only in adulthood. MZ B cells compensate for this early developmental inefficiency through cell density-dependent proliferation, ensuring the timely establishment of a stable pool. Collectively, these findings unveil critical roles of quorum sensing and immune system maturation in the maintenance of this vital B cell subset.

immunology↗

bioRxiv2024

Tissue resident memory CD4+ T cells are sustained by site-specific levels of self-renewal and replacement from precursors

Tissue-resident memory T cells (TRM) protect from repeat infections within organs and barrier sites. The breadth and duration of such protection is defined at minimum by three quantities; the rate at which new TRM are generated from precursors, their rate of self-renewal, and their rate of loss through death, egress, or differentiation. Quanti-fying these processes individually is challenging. Here we combine genetic fate mapping tools and mathematical models to untangle these basic homeostatic properties of CD4+ TRM in the skin and gut lamina propria (LP) of healthy adult mice. We show that CD69+CD4+ TRM in skin reside for [~]24 days and self-renew more slowly, such that clones halve in size approximately every 5 weeks; and approximately 2% of cells are replaced daily from precursors. CD69+CD4+ TRM in LP have shorter residencies ([~]14 days) and are maintained largely by immigration (4-6% per day). We also find evidence that the continuous replacement of CD69+CD4+ TRM at both sites derives from circulating effector-memory CD4+ T cells, in skin possibly via a local CD69- intermediate. Our approach maps the ontogeny of CD4+ TRM in skin and LP and exposes their dynamic and distinct behaviours, with continuous seeding and erosion potentially impacting the duration of immunity at these sites.

immunology↗

bioRxiv2024

A variational deep-learning approach to modeling memory T cell dynamics

Mechanistic models of dynamic, interacting cell populations have yielded many insights into the growth and resolution of immune responses. Historically these models have described the behavior of pre-defined cell types based on small numbers of phenotypic markers. The ubiquity of deep pheno-typing therefore presents a new challenge; how do we confront tractable and interpretable mathematical models with high-dimensional data? To tackle this problem, we studied the development and persistence of lung-resident memory CD4 and CD8 T cells (TRM) in mice infected with influenza virus. We developed an approach in which dynamical model parameters and the population structure are inferred simultaneously. This method uses deep learning and stochastic variational inference and is trained on the single-cell flow-cytometry data directly, rather than on the kinetics of pre-identified clusters. We show that during the resolution phase of the immune response, memory CD4 and CD8 T cells within the lung are phenotypically diverse, with subsets exhibiting highly distinct and time-dependent dynamics. TRM heterogeneity is maintained long-term by ongoing differentiation of relatively persistent Bcl-2hi CD4 and CD8 TRM subsets which resolve into distinct functional populations. Our approach yields new insights into the dynamics of tissue-localized immune memory, and is a novel basis for interpreting time series of high-dimensional data, broadly applicable to diverse biological systems.

immunology↗

bioRxiv2023

Cell age, not chronological age, governs the dynamics and longevity of circulating CD4+ memory T cells

Quantifying the kinetics with which memory T cell populations are generated and maintained is essential for identifying the determinants of the duration of immunity. The quality and persistence of circulating CD4+ effector memory (TEM) and central memory (TCM) T cells in mice appear to shift with age, but it is unclear whether these changes are driven by the aging host environment, by cell age effects, or both. Here we address these issues by combining DNA labelling methods, established fate-mapping systems, a novel reporter mouse strain, and mathematical models. Together, these allow us to quantify the dynamics of both young and established circulating memory CD4+ T cell subsets, within both young and old mice. We show that that these cells and their descendents become more persistent the longer they reside within the TCM and TEM pools. This behaviour may limit memory CD4 T cell diversity by skewing TCR repertoires towards clones generated early in life, but may also compensate for functional defects in new memory cells generated in old age. Author summaryOur long-term protection against infections depends in part on the maintenance of diverse populations of memory CD4 T cells, which are made in response to the initial exposure to the pathogen or a vaccine. These cells are not long-lived, but instead are maintained dynamically at a clonal level through loss and division. Understanding how immune memory persists therefore requires measuring these rates of these processes, and how they might change with age. Here we combine experiments in mice with mathematical models to show that memory CD4 T cells exhibit complex dynamics but increase their capacity to survive as they age. This dynamic implies that as individuals age, their memory CD4 T cell populations become enriched for older clones. This established memory may compensate for functional defects in new T cell responses generated later in life.

immunology↗

bioRxiv2019

Fate mapping quantifies the dynamics of B cell development and activation throughout life

Follicular mature (FM) and germinal centre (GC) B cells underpin humoral immunity but the dynamics of their generation and maintenance are not clearly defined. Here we exploited a fate-mapping system in mice that tracks B cells as they develop into peripheral subsets, together with a cell division fate reporter mouse and mathematical models. We find that FM cells are kinetically homogeneous, recirculate freely, continually replenished from transitional populations, and self-renew rarely. In contrast, GC B cell lineages persist for weeks with rapid turnover and site-specific dynamics. Those in the spleen derive from transitional cells and are kinetically homogeneous, while those in lymph nodes derive from FM B cells and comprise both transient and persistent clones. These differences likely derive from the nature of antigen exposure at the different sites. Our integrative approach also reveals how the host environment drives cell-extrinsic, age-related changes in B cell homeostasis.

immunology↗

bioRxiv2019

A single wave of monocytes is sufficient to replenish the long-term Langerhans cell network after immune injury

Embryo-derived Langerhans cells (eLC) are maintained within the sealed epidermis without contribution from circulating cells. When the network is perturbed by transient exposure to ultra-violet light, short-term LC are temporarily reconstituted from an initial wave of monocytes, but thought to be superseded by more permanent repopulation with undefined LC precursors. However, the extent to which this mechanism is relevant to immune-pathological processes that damage LC population integrity is not known. Using a model of allogeneic hematopoietic stem cell transplantation, where allo-reactive T cells directly target eLC, we have asked if and how the original LC network is ultimately restored. We find that donor monocytes, but not dendritic cells, are the precursors of the long-term LC in this context. Destruction of eLC leads to recruitment of a single wave of monocytes which engraft in the epidermis and undergo a sequential pathway of differentiation via transcriptionally distinct EpCAM+ precursors. Monocyte-derived LC acquire the capacity of self-renewal, and turn-over in the epidermis was remarkably similar to that of steady state eLC. However, we have identified a bottleneck in the differentiation and survival of epidermal monocytes, which together with the slow turn-over of mature LC limits repair of the network. Furthermore, replenishment of the LC network leads to constitutive entry of cells into the epidermal compartment. Thus, immune injury triggers functional adaptation of mechanisms used to maintain tissue-resident macrophages at other sites, but this process is highly inefficient in the skin.\n\nHighlightsO_LIImmune injury leads to recruitment of a single wave of monocytes to replace resident Langerhans cells (LC).\nC_LIO_LIDC lineage cells cannot become long-term replacement LC.\nC_LIO_LIThe size of the re-emerging network is controlled by density-dependent division of mature LC.\nC_LIO_LIImmune injury and inefficient repopulation by monocyte-derived cells lead to a permanently altered LC niche.\nC_LI\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC=\"FIGDIR/small/617514v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (32K):\norg.highwire.dtl.DTLVardef@1c08563org.highwire.dtl.DTLVardef@753e0corg.highwire.dtl.DTLVardef@13ca3cforg.highwire.dtl.DTLVardef@269ffc_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗