Biology subjects

Nageswaran, G.

Publications and source records attributed to Nageswaran, G..

6 recordsLinked to original sources

bioRxiv2026

Spatiotemporal profiling of T cell repertoires in Lynch syndrome reveals convergent immune responses through neoplastic progression

Surveillance of individuals with Lynch syndrome (LS), who are carriers of heterozygous inactivating mismatch repair (MMR) gene mutations that predispose to colorectal cancer, enables the study of tumour-immune coevolution during tumour initiation. Somatic loss of MMR activity in the LS colon leads to the accrual of cancer driver mutations, and also of neoantigens likely to generate an adaptive immune response. However, the spatial and temporal immune dynamics in colon and peripheral blood are uncharacterised. Here we show that the neoplastic evolution of mismatch repair deficient (MMRd) clones leads to large-scale and sustained reorganisation of the T-cell repertoire in colon and peripheral blood. We performed dense spatiotemporal profiling of T cell receptor (TCR) repertoires from 109 colonic biopsies (11 tumour samples, 98 normal bowel) from seven individuals, with eight matched blood repertoires. We additionally analysed 13 colorectal polyp repertoires from eight participants, 286 cross sectional blood repertoires from 242 participants (198 LS and 44 non-LS) and 52 longitudinal peripheral blood samples from 26 individuals with LS. We detected tumour-associated T cell clones, some of which were widely present in normal bowel tissue and also detectable in peripheral blood. Sequence similarity analysis revealed conserved TCR architectures across tissue compartments and recurrent clustering patterns between patients, that were not present in non-Lynch controls, consistent with convergent MMRd-associated antigen-driven immune selection. We identified systemic signatures associated with local tumour immune activity and revealed evidence of structured repertoire remodelling before overt malignancy. Longitudinal profiling revealed frequent turnover of low-abundance clonotypes, whereas highly abundant clonotypes persisted for several years. Collectively, our data defines the local and circulating TCR landscape associated with colonic neoplasia in LS, and provides a framework for LS blood-based immune monitoring, early interception and biomarker development.

immunology↗

bioRxiv2025

Temporal Dynamics of Antigen-Specific T Cell Expansion in Primary SARS-CoV-2 Infection

Quantifying T cell response during primary infection in humans is crucial for understanding adaptive immunity. Leveraging a controlled human challenge to SARS-CoV-2, we characterized antigen-specific T cell response within and across individuals. Notably, individual clones reached similar maximum frequencies despite differences in the timing of their peak expansion. Mathematical modeling showed that this observation is consistent with precursor frequency, but not TCR signal strength, as the source of inter-clonal variability. Single-cell profiling revealed distinct temporal programs for CD4+ and CD8+ T cells, with CD4+ cells expanding earlier but contracting to a lower frequency. Clones with similar receptors, likely recognizing the same antigen, expanded at similar times. Together, these findings highlight how clone-intrinsic properties such as precursor frequency and lineage shape T cell clonal kinetics. These insights provide a quantitative framework for understanding T cell response in humans, with implications for vaccine design.

biophysics↗

bioRxiv2025

The T-cell receptor repertoire of wild mice

Wild animals live in a pathogen-rich environment, and are normally infected with a wide range of micro- and macro-parasites. Wild animals T cells are central to the effectiveness of their adaptive immune response in ameliorating the effect of these infections. Here we have investigated the T-cell receptor (TCR) repertoire of wild mice to investigate how it varies in animals of different ages and sex, and from different sites. We sequenced the TCR alpha and beta chains of CD4+ and CD8+ T-cells of 65 wild Mus musculus domesticus from two UK sites. We analysed repertoire richness and diversity finding that wild mice have large TCR repertoires. Repertoire richness, which measures the breadth of the repertoire, was not significantly affected by mouse age or sex, suggesting that wild mice maintain the capacity to respond to novel antigens throughout their lives. In contrast, repertoire diversity (measured by Shannons index) was affected by a mouse sex-by-age interaction. This low diversity, coupled with constant richness, points to older mice having comparatively more highly abundant clones in their repertoires, perhaps due to chronic exposure to persistent pathogens in their environment. These findings provide a novel description of the wild mouse TCR, revealing an immune system that balances maintaining a broad response capacity with developing strong, lasting responses to infections in the natural environment.

immunology↗

bioRxiv2025

Evolution of T cell responses in the tuberculin skin test reveals generalisable Mtb-reactive T cell metaclones.

T cells contribute to immune protection and pathogenesis in tuberculosis, but measurements of polyclonal responses have failed to resolve correlates of outcome. We report the first temporal evaluation of the human in vivo clonal repertoire of Mtb-reactive T cell responses, by T cell receptor (TCR) sequencing at the site of a standardised antigenic challenge. Initial recruitment of non-Mtb reactive T cells is followed by enrichment of Mtb-reactive clones arising from oligoclonal T cell proliferation. We introduce a modular computational pipeline, Metaclonotypist, to sensitively cluster distinct TCRs with shared epitope specificity, which we apply here to establish a catalogue of public Mtb-reactive HLA-restricted T cell metaclones. Although most in vivo Mtb-reactive T cells are private, 10 metaclones were sufficient to identify Mtb-T cell reactivity across our study population (N[≥]128), indicating striking population level immunodominance of specific TCR-peptide interactions that may offer novel approaches to patient stratification and vaccine development.

immunology↗

bioRxiv2023

Spatially-resolved profiling of the T-cell receptor repertoire in archival clinical specimens using FUME-TCRseq

Genomic analysis of the T-cell receptor (TCR) reveals the strength, breadth and clonal dynamics of the adaptive immune response to pathogens or cancer. The diversity of the TCR repertoire, however, means that sequencing is technically challenging, particularly for samples with low quality, degraded nucleic acids. Here, we have developed and validated FUME-TCRseq, a robust and sensitive RNA-based TCR sequencing methodology that is suitable for formalin-fixed paraffin-embedded samples and low amounts of input material. FUME-TCRseq incorporates unique molecular identifiers into each molecule of cDNA, allowing correction for sequencing errors and PCR bias. We used RNA extracted from colorectal and head and neck cancers to benchmark the accuracy and sensitivity of FUME-TCRseq against existing methods, and found excellent concordance between the datasets. Furthermore, FUME-TCRseq detected more clonotypes than a commercial RNA-based alternative, with shorter library preparation time and significantly lower cost. The high sensitivity and the ability to sequence RNA of poor quality and limited amount enables quantitative analysis of small numbers of cells from archival tissue sections, which is not possible with other methods. To demonstrate this we performed spatially-resolved FUME-TCRseq of colorectal cancers using macrodissected archival samples, revealing the shifting T-cell landscapes at the transition to an invasive phenotype, and between tumour subclones containing distinct driver alterations. In summary, FUME-TCRseq represents an accurate, sensitive and low-cost tool for the characterisation of T-cell repertoires, particularly in samples with low quality RNA that have not been accessible using existing methodology.

immunology↗

bioRxiv2022

Large clones of pre-existing T cells drive early immunity against SARS-COV-2 and LCMV infection.

We analyzed the dynamics of the earliest T cell response to SARS-COV-2. A wave of TCRs strongly but transiently expand during infection, frequently peaking the same week as the first positive PCR test. These expanding TCR CDR3s were enriched for sequences functionally annotated as SARS-COV-2 specific. Most epitopes recognized by the expanding TCRs were highly conserved between SARS-COV-2 strains, but not with circulating human coronaviruses. Many expanding CDR3s were also present at high precursor frequency in pre-pandemic TCR repertoires. A similar set of early response TCRs specific for lymphocytic choriomeningitis virus epitopes were also found at high frequency in the pre-infection naive repertoire. High frequency naive precursors may allow the T cell response to respond rapidly during the crucial early phases of acute viral infection. One-Sentence SummaryHigh frequency naive precursors underly the rapid T cell response during the crucial early phases of acute viral infection.

immunology↗