Biology subjects

Yates, T. B.

Publications and source records attributed to Yates, T. B..

4 recordsLinked to original sources

bioRxiv2026

Divergent phenotypic and functional roles of human T follicular helper cells from infancy to adulthood

Antibody responses to T-dependent antigens are suboptimal in young children, yet the evolution of T follicular helper cell (Tfh) function across the human lifespan remains poorly defined. Using human tonsils, a physiologically relevant and abundant source of Tfh, we investigated age-associated differences in their repertoire and functional programs. Pediatric tonsils were enriched for cytokine-expressing Tfh subsets with increased clonal diversity and phenotypic plasticity. However, in response to influenza antigens, they exhibited reduced Th1 polarization, diminished IL-21 production, and limited B cell help. Across ages, high neutralizing flu antibody responses were associated with robust Tfh1 activation, which was ICOS dependent in adults but not in children. Interestingly, Tfh depletion strategies revealed enhanced Tfh differentiation from distinct precursors in pediatric donors, yet antibody responses during early life were less reliant on Tfh help. Together, these findings define developmentally programmed differences in Tfh differentiation and function with implications for pediatric vaccine design.

immunology↗

bioRxiv2026

A tonsil organoid model reveals Epstein-Barr virus infected germinal center B cell states during primary infection

Epstein-Barr virus (EBV) colonizes secondary lymphoid tissues to establish persistent infection and is strongly associated with malignancy and autoimmunity. Our understanding of EBV infection biology is hindered by a lack of models that capture infected B cell activity in the lymphoid tissue microenvironment. We therefore developed an EBV human tonsil organoid model to evaluate key B cell states and antiviral responses, including after primary infection. EBV promoted B cell differentiation into germinal center (GC)-like phenotypes and transcriptomic analyses highlighted numerous B cell transcriptional programs unique to EBV-infected cells. B cell receptor repertoire analysis revealed that most EBV-infected B cells underwent class switching but only rarely participated in somatic hypermutation. CD4 T cells, highly activated by organoid infection, limited EBV+ B cell outgrowth. Our findings demonstrate human tonsil organoids as a physiologically relevant model to investigate key aspects of EBV immunity and pathogenesis.

immunology↗

bioRxiv2023

The Plasminogen-Apple-Nematode (PAN) domain suppresses JA/ET defense pathways in plants

Suppression of immune response is a phenomenon that enables biological processes such as gamete fertilization, cell growth, cell proliferation, endophyte recruitment, parasitism, and pathogenesis. Here, we show for the first time that the Plasminogen-Apple-Nematode (PAN) domain present in G-type lectin receptor-like kinases is essential for immunosuppression in plants. Defense pathways involving jasmonic acid and ethylene are critical for plant immunity against microbes, necrotrophic pathogens, parasites, and insects. Using two Salix purpurea G-type lectin receptor kinases, we demonstrated that intact PAN domains suppress jasmonic acid and ethylene signaling in Arabidopsis and tobacco. Variants of the same receptors with mutated residues in this domain could trigger induction of both defense pathways. Assessment of signaling processes revealed significant differences between receptors with intact and mutated PAN domain in MAPK phosphorylation, global transcriptional reprogramming, induction of downstream signaling components, hormone biosynthesis and resistance to Botrytis cinerea. Further, we demonstrated that the domain is required for oligomerization, ubiquitination, and proteolytic degradation of these receptors. These processes were completely disrupted when conserved residues in the domain were mutated. Additionally, we have tested the hypothesis in recently characterized Arabidopsis mutant which has predicted PAN domain and negatively regulates plant immunity against root nematodes. ern1.1 mutant complemented with mutated PAN shows triggered immune response with elevated WRKY33 expression, hyperphosphorylation of MAPK and resistant to necrotrophic fungus Botrytis cinerea. Collectively, our results suggest that ubiquitination and proteolytic degradation mediated by the PAN domain plays a role in receptor turn-over to suppress jasmonic acid and ethylene defense signaling in plants.

plant biology↗

bioRxiv2021

Core cysteine residues in the PAN domain are critical for HGF/c-MET signaling

The Plasminogen-Apple-Nematode (PAN) domain, with a core of four to six cysteine residues, is found in > 28,000 proteins across 959 genera but its role in protein function is not fully understood. The PAN domain was initially characterized to be present in numerous proteins including hepatocyte growth factor (HGF). Dysregulation of HGF-mediated signaling results in numerous deadly cancers. All biological impacts of HGF in cell proliferation are triggered by binding of HGF to its cell surface receptor, cellular mesenchymal-epidermal transition (c-MET). Here, we show that four PAN domain cysteine residues are essential for HGF/c-MET signaling. Mutating these residues resulted in retardation of perinuclear localization, cellular internalization of HGF and its receptor, c-MET, and c-MET ubiquitination. Our observations indicate that the PAN domain of HGF is required for the c-MET binding and subsequent c-MET autophosphorylation and phosphorylation of its downstream targets, protein kinase B (AKT), extracellular signal-regulated kinase (ERK), and signal transducer and activator of transcription 3 (STAT3). Furthermore, transcriptional activation of HGF/c-MET signaling-related genes including matrix metalloproteinase-9 (MMP9), ETS translocation variant 1, 4, and 5 (ETV1, ETV4, ETV5), and early growth response 1 (EGR1) was impaired and cell proliferation was attenuated. These results suggest that core cysteine residues in the PAN domain are critical for HGF/c-MET interaction, c-MET mediated signal transduction, and cell survival. Thus, targeting the PAN domain of HGF may represent a mechanism for selectively regulating the binding and activation of the c-MET pathway. SignificanceHGF/c-MET signaling induces multifunctional cellular responses. Dysregulation of HGF/c-MET signaling cascade can lead to tumorigenesis by transforming normal cells to tumor cells. This work defines the importance of core cysteine residues in the PAN domain of HGF in downstream activation of HGF/c-MET signaling. To understand the role of cysteines in the PAN domain, PAN mutants of HGF were used to stimulate c-MET signaling in cells and the impact was delineated by determining phosphorylation and transcription of downstream targets. Mutations in core cysteines in the HGF-PAN domain completely blocked downstream phosphorylation and perinuclear accumulation of c-MET. These results suggest an indispensable role for the cysteine-rich PAN domain in HGF/c-MET interaction and could set the stage for future therapies that selectively disrupt the MET signaling cascade with limited off-target effects in tumors overexpressing HGF/c-MET.

cell biology↗