Biology subjects

McLaren, J. E.

Publications and source records attributed to McLaren, J. E..

4 recordsLinked to original sources

bioRxiv2026

Adaptive-like features of the γδ TCR couple chronic BTNL recognition to NK-like tissue immunity

Intestinal V{gamma}4 {gamma}{delta} intraepithelial lymphocytes (IELs) persistently bind the constitutively expressed epithelial ligand BTNL3/8 through germline-encoded T cell receptor (TCR) determinants. While they resemble innate-like T cells such as NKT cells, unlike these populations, V{gamma}4 IELs encounter ligand only after thymic development. Moreover, unlike conventional {beta} T cells, V{gamma}4 IELs sustain persistent physiological ligand engagement without becoming exhausted. Here, using biophysical, functional, and multimodal single-cell approaches, we show how V{gamma}4 IELs address this challenge. While germline-encoded TCR regions broadly mediate BTNL3 recognition, productive activation requires additional non-germline TCR features that license responsiveness to BTNL3/8 and enable local selection in the gut. Rather than driving exhaustion, BTNL3/8 reactivity directly promotes expression of an NK-like program marked by adaptor molecules that license innate-like signaling in healthy tissue. These findings reveal how combined innate and adaptive features of the {gamma}{delta}TCR enable durable tissue specialization under conditions of persistent physiological ligand engagement.

immunology↗

bioRxiv2025

Cytomegalovirus-induced T cell responses accelerate Alzheimer's disease progression in mice

Infections have long been implicated as causative factors in Alzheimers disease (AD). Multiple studies have further suggested a key role for herpesviruses, such as cytomegalovirus (CMV). Using transgenic 3xTg-AD mice, we demonstrate that systemic infection with the {beta}-herpesvirus murine cytomegalovirus (MCMV) accelerates the development of cognitive decline, tauopathy, and synaptic loss in the hippocampus, all of which are key features of AD. Accelerated disease progression after infection was associated with substantial lymphocyte infiltration into the brain dominated by CD8+ T cells specific for MCMV. Moreover, T cell receptor analyses revealed that these responses were clonally diverse, suggesting that multiple viral antigens were targeted in the brain during chronic infection with MCMV. T cell depletion during virus chronicity rescued infection-induced cognitive decline. In addition, antiviral drug treatment reduced lymphocytic infiltrates in the brain and reversed cognitive decline, suggesting potential clinical utility. These data provide a mechanistic link between chronic viral infections and the development of AD.

immunology↗

bioRxiv2020

CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor

CD8+ T cells are inherently cross-reactive and recognize numerous peptide antigens in the context of a given major histocompatibility complex class I (MHCI) molecule via the clonotypically expressed T cell receptor (TCR). The lineally expressed coreceptor CD8 interacts coordinately with MHCI at a distinct and largely invariant site to slow the TCR/peptide-MHCI (pMHCI) dissociation rate and enhance antigen sensitivity. However, this biological effect is not necessarily uniform, and theoretical models suggest that antigen sensitivity can be modulated in a differential manner by CD8. We used an intrinsically controlled system to determine how the relationship between the TCR/pMHCI interaction and the pMHCI/CD8 interaction affects the functional sensitivity of antigen recognition. Our data show that modulation of the pMHCI/CD8 interaction can reorder the agonist hierarchy of peptide ligands across a spectrum of affinities for the TCR. SIGNIFICANCESufficient immune coverage of the peptide universe within a finite host requires highly degenerate T cell receptors (TCRs). However, this inherent need for antigen cross-recognition is associated with a high risk of autoimmunity, which can only be mitigated by a process of adaptable specificity. We describe a mechanism that resolves this conundrum by allowing individual clonotypes to focus on specific peptide ligands without alterations to the structure of the TCR.

immunology↗

bioRxiv2019

CD4+ T follicular helper (Tfh) cells in human tonsil and blood are clonally convergent, but divergent from non-Tfh CD4+ cells

T follicular helper (Tfh) cells are fundamental for B cell selection and antibody maturation in germinal centers. Circulating Tfh (cTfh) cells constitute a minor proportion of the CD4+ T cells in peripheral blood, but their clonotypic relationship to Tfh populations resident in lymph nodes and the extent to which they differ from non-Tfh CD4+ cells has been unclear. Using donor-matched blood and tonsil samples we investigated T cell receptor (TCR) sharing between tonsillar Tfh cells and peripheral Tfh and non-Tfh cell populations. TCR transcript sequencing revealed considerable clonal overlap between peripheral and tonsillar Tfh cell subsets as well as a clear distinction between Tfh and non-Tfh cells. Furthermore, influenza-specific cTfh cell clones derived from blood could be found in the repertoire of tonsillar Tfh cells. Therefore, human blood samples can be used to gain insight into the specificity of Tfh responses occurring in lymphoid tissues, provided cTfh subsets are studied.

immunology↗