Celebrating PhD success for Yuta & Josh!

...we quantify the amount of information (in bits) that T cell receptor (TCR) sequence features provide about antigen specificity. We identify informative features by their degree of conservation among antigen-specific receptors relative to null expectations. We find that TCR specificity synergistically depends on the hypervariable regions of both receptor chains, with a degree of synergy that strongly depends on the ligand.

For all the T cell receptor sequencers out there, the latest version of our analysis pipeline Decombinator 5.0 is live, and now on PiPy for greater ease of installtion. Can now run the whole pipeline using a single command. Much faster and more memory efficient. Thanks to Matt Cowley for a huge amount of work !

"We will test the hypothesis that dominant Mycobacterium tuberculosis-reactive T cells in antiretroviral-treated people living with HIV have restricted clonality, target different antigens and exhibit different functionality, compared to those of HIV-negative individuals. We will identify which of these T cell traits impact on macrophage control of Mtb-growth, and predict disease-risk in multiple independent cohorts sampled from the general population."

"We single-cell sequenced 5.7 million T cells from ten donors' autologous blood and tonsils and sought to answer key questions about T cell receptor biology previously unanswerable by smaller-scale experiments. We identified distinct clonal expansions and distributions in blood compared to tonsils, with surprisingly low (1-7%) clonal sharing. These few shared clones exhibited divergent phenotypes across bodily sites."

"Triage blood RNA signatures for pulmonary TB are unlikely to provide advantages over molecular microbiological testing for those who can produce sputum, but should be targeted to sputum-scarce individuals to trigger sputum induction or invasive sampling."

“RNA biomarkers showed better clinical utility to guide confirmatory tuberculosis testing for people living with HIV before ART initiation than symptom-based screening, but their performance did not exceed that of CRP and fell short of WHO recommended targets. Interferon-independent approaches might be required to improve accuracy of host-response biomarkers to support tuberculosis screening before ART initiation.”

“…detailed time series data can serve as a Rosetta stone for epithelial and immune cell responses and reveals early dynamic responses associated with protection against infection.”

“These results demonstrate the power of coincidence analysis to reveal the sequence determinants of epitope binding in receptor repertoires.”

“Post-COVID radiological inflammation and fibrosis show evidence of shared antigen-specific T cell responses, suggesting a role for therapies targeting T cells in limiting post-COVID lung damage.”

“RNA biomarkers show better accuracy and clinical utility than CRP to trigger confirmatory TB testing in patients with TB lymphadenitis and TB pericarditis, but still fall short of the WHO TPP for TB triage tests.”

“Type I interferon responses contribute to host immune protection in mycobacterial infection by recruitment of myeloid cells to the site of disease.”

“Single-gene transcripts are equivalent to multi-gene signatures for detection of subclinical TB, with consistent performance across settings. Single transcripts demonstrate potential clinical utility to stratify treatment, particularly when used in combination with IGRA in low burden settings.”

“These data help to improve our understanding of the immune response to Mtb and enable further exploration of bulk transcriptomic data through context-specific cellular deconvolution.”

“The MX1 response achieved superior diagnostic accuracy in early infection, correlation with viral load and identification of virus culture positivity, with potential to stratify patients for time sensitive antiviral treatment. IFI27 achieved superior diagnostic accuracy across the time course of symptomatic infection. Compared to blood, measurement of these responses in nasal mucosal samples was less sensitive and did not discriminate between early and late phases of infection.”

“tidytcells is a lightweight, platform-independent Python package that provides easy-to-use standardization tools specifically designed for TR nomenclature.”

“…we show that the sequences of paired TCRα and TCRβ are not independent within the repertoires of TCRs specific for most epitopes examined. We show that this sequence restriction can be quantified using a mutual information framework, can be learnt by co-evolution models without using a training set of known pairs and allows de novo predictions of TCRα/TCRβ pairing.”

“We anticipate that contrastive learning will be a useful paradigm to decode the rules of TCR specificity. “

"Meta-analyses and Mendelian randomisation analyses revealed that reduced classical IL-6 signalling was associated with lower odds of TB disease, a finding replicated using multiple, independent SNP instruments and 2 separate exposure variables. Our findings establish a causal relationship between IL-6 signalling and the outcome of Mtb infection, suggesting IL-6 antagonists do not increase the risk of TB disease and should be investigated as adjuncts in treatment."

Weekly Joint Lab Meetings

Seminars

Benny Chain Festschrift Research Symposium

In celebration of Benny Chain’s scientific journey on his 70th birthday - from DC biology to computational systems immunology.

EMBO workshop. 09 – 12 February 2025 | Hyderabad, Telangana, India

"This EMBO Workshop will bring together researchers who study Mtb-host responses from bacteria to cell to organism. The aim of this EMBO Workshop is to enhance the understanding of heterogeneous biology and disease pathogenesis, which will inform novel strategies for treatment and prevention."