Biology subjects

Hogan, T.

Publications and source records attributed to Hogan, T..

7 recordsLinked to original sources

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↗

bioRxiv2025

Single cell analysis of ovarian immune cells during homeostasis and hormonal flux reveals dynamic changes in NK and B cell populations in the periovulatory phase

The mammalian ovary is the dynamic end-organ of the hypothalamic pituitary ovarian axis. In this coordinated system, ovarian cells undergo continuous cycles of apoptosis, proliferation, and differentiation. These changes parallel fluctuations in ovarian hormones such as estradiol (E2); however, the ovarian immune microenvironment during high-E2 and low-E2 states is not fully understood. We induced a high-E2 state in the mouse ovary by stimulation via gonadotropin treatment. Single-cell RNA sequencing and flow cytometry analysis of ovarian leukocytes revealed abundant mature NK cells, B1 and B2 cells, CD8+ T cells, CD4+ T cells, mature CD4-CD8-T cells, T regulatory cells, and distinct myeloid subsets, including Trem2+ and Apoe+ macrophages. In vivo labeling of circulating cells determined that the vast majority of ovarian leukocytes were tissue-resident. Following gonadotropin treatment, the frequency of NK cells increased two-fold, while B1 cell frequency was reduced by half. Consistently, flow cytometric analysis revealed an increase in mature CD11b+ NK cells following gonadotropin treatment. Gonadotropin treatment also increased cell-cell signaling by myeloid cells at the expense of NK cells. Our findings reveal a diverse resident immune landscape in the ovary that responds robustly to hormonal changes. These findings have implications for a role for immune cells in ovarian physiology and functional dysregulation.

immunology↗

bioRxiv2024

A linear ontogeny accounts for the development of naive, memory and tumour-infiltrating regulatory T cells in mice

Foxp3+ Regulatory T cells (Treg) are a subset of CD4+ T cells that play critical functions in maintaining tolerance to self antigens and suppressing autoimmunity, regulating immune responses to pathogens and have a role in the pathophysiology of anti-tumoural immunity. Treg ontogeny is complex since they are generated following recognition of self antigens in the thymus during normal T cell development (thymic Treg), but are also induced from mature conventional T cells when activated by foreign antigen with appropriate additional cues (inducible Treg). How these distinct ontogenic pathways contribute to the maintenance and function of the mature Treg compartment in health and disease remains unclear. Here, we use a combination of fate mapping approaches in mice to map the ontogeny of Treg subsets throughout life and estimate rates of production, loss and self-renewal. We find that naive and effector/memory (EM) Treg subsets exhibit distinct dynamics but are both continuously replenished by de novo generation throughout life. Using an inducible Foxp3-dependent Cre fate reporter system, we show that naive Treg and not conventional T cells, are the predominant precursors of EM Treg in adults. Tonic development of new EM Treg is not influenced by foreign antigens from commensals, rather suggesting a role for self recognition. To investigate the ontogeny of Treg development in malignant disease, we used the same fate reporter systems to characterise the Treg infiltrate of three different model tumours. In all three cases, we found that Treg derived from pre-existing, EM Treg. Together, these results reveal a predominantly linear pathway of Treg development from thymic origin to EM Treg associated with pathophysiology of malignant disease, that is driven by self antigen recognition throughout.

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↗

bioRxiv2022

Defining the dynamics of naive CD4 and CD8 T cells across the mouse lifespan

Naive CD4 and CD8 T cells are cornerstones of adaptive immunity, but the dynamics of their establishment early in life and how their kinetics change as they mature following release from the thymus are poorly understood. Further, due to the diverse signals implicated in naive T cell survival, it has been a long-held and conceptually attractive view that they are sustained by active homeostatic control as thymic activity wanes. Here we employ multiple experimental systems to identify a unified model of naive CD4 and CD8 T cell population dynamics across the mouse lifespan. We infer that both subsets divide rarely and progressively increase their survival capacity with cell age. Strikingly, this simple model captures naive CD4 T cell dynamics throughout life. In contrast, we find that newly generated naive CD8 T cells are lost more rapidly during the first 3-4 weeks of life, likely due to increased recruitment into memory. We find no evidence for elevated division rates in neonates, or for feedback regulation of naive T cell numbers at any age. We show how confronting mathematical models with diverse datasets can reveal a quantitative and remarkably simple picture of naive T cell dynamics from birth into old age.

immunology↗

bioRxiv2020

Distinct neural substrates of individual differences in components of reading comprehension in adults with or without dyslexia

Reading comprehension is a complex task that depends on multiple cognitive and linguistic processes. According to the updated Simple View of Reading framework, in adults, individual variation in reading comprehension can be largely explained by combined variance in three component abilities: (1) decoding accuracy, (2) fluency, and (3) language comprehension. Here we asked whether the neural correlates of the three components are different in adults with dyslexia as compared to typically-reading adults and whether the relative contribution of these correlates to reading comprehension is similar in the two groups. We employed a novel naturalistic fMRI reading task to identify the neural correlates of individual differences in the three components using whole-brain and literature-driven regions-of-interest approaches. Across all participants, as predicted by the simple view framework, we found distinct patterns of associations with linguistic and domain-general regions for the three components, and that the left-hemispheric neural correlates of language comprehension in the angular and posterior temporal gyri made the largest contributions to explaining out-of-scanner reading comprehension performance. These patterns differed between the two groups. In typical adult readers, better fluency was associated with greater activation of left occipitotemporal regions, better comprehension with lesser activation in prefrontal and posterior parietal regions, and there were no significant associations with decoding. In adults with dyslexia, better fluency was associated with greater activation of bilateral inferior parietal regions, better comprehension was associated with greater activation in some prefrontal clusters and lower in others, and better decoding skills were associated with lesser activation of bilateral prefrontal and posterior parietal regions. Extending the behavioral findings of skill-level differences in the relative contribution of the three components to reading comprehension, the relative contributions of the neural correlates to reading comprehension differed based on dyslexia status. These findings reveal some of the neural correlates of individual differences in the three components and the underlying mechanisms of reading comprehension deficits in adults with dyslexia.

neuroscience↗

bioRxiv2019

Differential impact of self and environmental antigens on the ontogeny and maintenance of CD4+ T cell memory

Laboratory mice develop populations of circulating memory CD4+ T cells in the absence of overt infection. We have previously shown that these populations are replenished from naive precursors at high levels throughout life (Gossel et al., 2017). However, the nature, relative importance and timing of the forces generating these cells remain unclear. Here, we tracked the generation of memory CD4+ T cell subsets in mice housed in facilities differing in their dirtiness. We found evidence for sequential naive to central memory to effector memory development, and confirmed that both memory subsets are heterogeneous in their rates of turnover. We also inferred that early exposure to self and environmental antigens establishes persistent memory populations at levels determined largely, though not exclusively, by the dirtiness of the environment. After the first few weeks of life, however, these populations are continuously supplemented by new memory cells at rates that are independent of environment.

immunology↗