Biology subjects

Robins, H. S.

Publications and source records attributed to Robins, H. S..

8 recordsLinked to original sources

bioRxiv2025

Shared TCRs in peripheral blood offer robust celiac disease classification independent of gluten Intake

Background and AimsCeliac disease (CeD) is a chronic digestive autoimmune disorder affecting approximately 1% of the worldwide population. It is driven by T cells activated by specific HLA-DQ2 or HLA-DQ8 molecules leading to the destruction of intestinal villi. We aimed to characterize shared CeD-specific T cells in patients on and off a gluten-free diet (GFD) from a large cohort of cases and controls. MethodsWe performed bulk TCR{beta} immune sequencing of the peripheral blood of 1,604 biopsy-confirmed CeD patients (1,339 on GFD, 265 on normal diet) and 1,100 controls. We identified over 300 TCR{beta}s enriched in CeD cases versus controls in an HLA-aware manner, controlling for CeD risk alleles. ResultsCeD-associated TCR{beta}s were found to be more predictive of disease than previously characterized gliadin and glutenin-binding TCRs in a validation cohort. Furthermore, the clonal breadth of these TCR{beta}s was associated with increased intestinal damage. Immune sequencing of the peripheral blood also uncovered repertoire-level differences between CeD patients and controls. CeD patients displayed significantly higher productive clonality compared to age-matched controls as well as expansion of TCR{beta}s specific to cytomegalovirus (CMV) and Epstein-Barr Virus (EBV). ConclusionsThese findings underscore the value of unbiased immune repertoire sequencing to identify novel biomarkers for autoimmune disease and to discover new disease mechanisms which can improve both diagnosis and treatment of disease.

immunology↗

bioRxiv2025

Multi-centered T cell repertoire profiling identifies novel alterations in the immune repertoire of individuals with inflammatory bowel disease and validates previous findings

IntroductionIBD is an incurable immune-mediated inflammatory disease (IMID), affecting the gut with a high rate of primary- and secondary-loss-of-response to therapy. By investigating the T cell receptor repertoire of individuals with IBD, novel therapeutic and preventive strategies can be identified, and a better understanding of IBD can be obtained. MethodsWhereas most studies have so far focused on the more diverse T cell receptor beta (TRB) repertoire, we here profiled the alpha (TRA) repertoire of three cohorts containing treatment-naive and treated individuals in addition to individuals living with the disease for >20 years, resulting in an exhaustive dataset containing the TRA repertoire of 2,151 individuals. ResultsUsing the generated datasets, we were able to replicate previous findings describing the expansion of Crohns-associated invariant T (CAIT) cells in individuals with Crohns disease (CD) in the three cohorts. Using a hypothesis-free statistical testing framework, we identified clonotypes that were associated with the disease at its different stages, e.g., at the time of diagnosis and decades post-diagnosis. By conducting a meta-analysis across the three cohorts, we were able to identify a set of clonotypes that were associated with the disease regardless of its stage. We validated our findings in a previously published independent test dataset from a German cohort, showing the robustness of the identified sets of clonotypes. ConclusionThe identified clonotypes are potential novel therapeutic targets to treat IBD, e.g., through targeted depletion. These clonotypes are also of major interest as they can be investigated in a targeted fashion to identify culprit antigen(s) in IBD.

immunology↗

bioRxiv2024

A Catalog of the Public T-cell Response to Cytomegalovirus

ECOclusters (Exposure Co-Occurrence clusters) are previously described groups of public T-cell receptors (TCRs) that tend to co-occur across T-cell repertoires from tens of thousands of donors. Each ECOcluster putatively represents the public T-cell response to a different prevalent immune exposure. We previously associated a 26,106-member ECOcluster with exposure to cytomegalovirus (CMV) and used it to define a sensitive, specific classifier for CMV seropositivity. Here, we provide the CMV-associated ECOcluster TCRs, describe the ECOcluster and explore some types of analysis that it enables. We assess the CMV specificity of its component HLA-COclusters (subgroups of co-occurring TCRs associated with the same HLA). We use TCR sequence similarity within HLA-ECOclusters to identify groups of TCRs putatively responding to the same antigen, and we find suggestions of different subgroups of CMV-exposed donors responding to different antigens. The CMV ECOcluster is the most complete catalog of the public T-cell response to CMV to date. We provide the CMV ECOcluster TCRs as a resource for research community use and exploration.

immunology↗

bioRxiv2024

Identifying immune signatures of common exposures through co-occurrence of T-cell receptors in tens of thousands of donors

BackgroundMemory T cells are records of clonal expansion from prior immune exposures such as infections, vaccines and chronic diseases. Some of the receptors of these expanded T cell clones in a typical immune repertoire are highly public (present in many individuals) because they respond to the same peptide from a prevalent immune exposure, presented by the same Human Leukocyte Antigen (HLA) allele. Only a tiny fraction of public T-cell receptor {beta} sequences (TCRs) have known associations with exposures or specific peptides. MethodsWe mined the TCR repertoires of tens of thousands of donors to define "ECOclusters": clusters of public TCRs that tend to occur in the same donors. First, we built models to infer donor HLA type from the TCR repertoire, then associated public TCRs with HLA alleles. Next, we derived co-occurrence clusters of TCRs responding to antigens presented by the same HLA allele, then combined those clusters by co-occurrence across HLA alleles. Each such cross-HLA ECOcluster putatively represents a public TCR signature of a single exposure. ResultsWe constructed sensitive, specific models to predict the presence of 220 HLA alleles from TCR repertoires and clustered 8,618,285 HLA allele-associated TCRs to define 11,058 ECOclusters. Using serologically labeled repertoires, we identified ECOclusters associated with HSV-1, HSV-2, EBV, Parvovirus, Toxoplasma gondii, Cytomegalovirus and SARS-CoV-2, and constructed sensitive, specific classifiers of exposure. ECOclusters represent a step toward deciphering the ledger of immune exposure history encoded by the T-cell repertoire.

immunology↗

bioRxiv2021

HLA Type and Chronic Viral Infection Impact Peripheral T-cell Receptor Sharing Between Unrelated Individuals

The human adaptive immune system must generate extraordinary diversity to be able to respond to all possible pathogens. The T-cell repertoire derives this high diversity through somatic recombination of the T-cell receptor (TCR) locus, a random process that results in repertoires that are largely private to each individual. However, certain factors such as low junctional diversity, thymic selection, and T-cell proliferation upon antigen exposure can affect TCR sharing among individuals. By immunosequencing the TCR{beta} variable region of 426 healthy individuals, we find that fewer than 1% of TCR{beta} clones are shared between individuals on average, consistent with largely private TCR{beta} repertoires. However, we detect a significant correlation between increased HLA allele sharing and increased number of shared TCR{beta} clones, with each additional shared HLA allele contributing to an increase in [~]0.01% of the total TCR{beta} clones being shared, supporting a key role for HLA type in shaping the immune repertoire. Surprisingly, we find that shared antigen exposure to CMV leads to fewer shared TCR{beta} clones, even after controlling for HLA, indicative of a largely private response to major viral antigenic exposure. Consistent with this hypothesis, we find that increased age is correlated with decreased overall TCR{beta} clone sharing, indicating that the pattern of private TCR{beta} clonal expansion is a general feature of the T-cell response to other infectious antigens. All of these factors contribute to shaping the TCR{beta} repertoire, and understanding their interplay has important implications for the use of T cells for therapeutics and diagnostics.

immunology↗

bioRxiv2018

Longitudinal immunosequencing in healthy people reveals persistent T cell receptors rich in public receptors

BackgroundThe adaptive immune system maintains a diversity of T cells capable of recognizing a broad array of antigens. Each T cells specificity and affinity for antigens is determined by its T cell receptors (TCRs), which together across all T cells form a repertoire of tens of millions of unique receptors in each individual. Although many studies have examined how TCR repertoires change in response to disease or drugs, few have explored the temporal dynamics of the TCR repertoire in healthy individuals.\n\nResultsHere we report immunosequencing of TCR {beta} chains (TCR{beta}) from the blood of three healthy individuals at eight time points over one year. TCR{beta} repertoires from samples of all T cells and memory T cells clearly clustered by individual, confirming that TCR{beta} repertoires are specific to individuals across time. This individuality was absent from TCR{beta}s from naive T cells, suggesting that these differences result from an individuals antigen exposure history. Many characteristics of the TCR{beta} repertoire (e.g., alpha diversity, clonality) were stable across time, although we found evidence of T cell expansion dynamics even within healthy individuals. We further identified a subset of \"persistent\" TCR{beta}s present across all time points, and these receptors were rich in clonal and public receptors.\n\nConclusionsOur results revealed persistent receptors that may play a key role in immune system maintenance. They further highlight the importance of longitudinal sampling of the immune system and provide a much-needed baseline for TCR{beta} dynamics in healthy individuals. Such a baseline should help improve interpretation of changes in the TCR{beta} repertoire during disease or treatment.

immunology↗

bioRxiv2017

Unbiased Definition Of A Shared T-Cell Receptor Motif Enables Population-Based Studies Of Tuberculosis

Peptide-specific T cells that are restricted by highly polymorphic major histocompatibility complex (MHC) proteins express diverse T-cell receptors (TCRs) that are rarely shared among unrelated individuals. T-cells can also recognize bacterial lipid antigens that bind the relatively non-polymorphic CD1 family of proteins. However, genetic variation in human CD1 genes and TCR diversity expressed by CD1-restricted T-cells have not been quantitatively determined. Here, we show that CD1B is nearly nucleotide-identical across all five continental ancestry groups, providing evidence for purifying selection during human evolution. We used CD1B tetramers loaded with a mycobacterial glycolipid antigen to isolate T-cells from four genetically unrelated South African adults and cataloged thousands of TCRs from in-vitro expanded T-cells using immunosequencing. We identified highly conserved motifs that were co-expressed as a functional heterodimer and significantly enriched among tetramer-positive T-cells sorted directly from peripheral blood. Finally, we show that frequencies of these TCR motifs are increased in the blood of patients with active tuberculosis compared to uninfected controls, a finding that is confirmed by ex-vivo frequencies of tetramer-positive T-cells determined by flow cytometry. These data provide a framework for unbiased definition of TCRs targeting lipid antigens, which can be tested for clinical associations independently of host genetic background.\n\nBrief SummaryWe used human genetics and immunosequencing to define a shared T-cell receptor motif that is specific for a mycobacterial lipid antigen and associated with tuberculosis independently of host genetic background.

immunology↗

bioRxiv2016

Multi-omic analysis of urothelial cancer patients treated with PD-L1 blockade demonstrates the contribution of both systemic and somatic factors to the biology of response and resistance

BackgroundInhibition of programmed death-ligand one (PD-L1) with atezolizumab can induce durable clinical benefit (DCB) in patients with metastatic urothelial cancers, including complete remissions in patients with chemotherapy refractory disease. Although mutation load and PD-L1 immune cell (IC) staining have been associated with response, they lack sufficient sensitivity and specificity for clinical use. Thus, there is a need to evaluate the peripheral blood immune environment and to conduct detailed analyses of mutation load, predicted neoantigens and immune cellular infiltration in tumors to enhance our understanding of the biologic underpinnings of response and resistance.\n\nMethods and FindingsThe goals of this study were to (1) evaluate the association of mutation load and predicted neoantigen load with therapeutic benefit, and (2) determine whether intratumoral and peripheral blood T cell receptor (TCR) clonality inform clinical outcomes in urothelial carcinoma treated with atezolizumab. We hypothesized that an elevated mutation load in combination with T cell clonal dominance among intratumoral lymphocytes prior to treatment or among peripheral T cells after treatment would be associated with effective tumor control upon treatment with anti-PD-L1 therapy. We performed whole exome sequencing (WES), RNA sequencing (RNA-seq), and T cell receptor sequencing (TCR-seq) of pre-treatment tumor samples as well as TCR sequencing of matched, serially collected peripheral blood collected before and after treatment with atezolizumab. These parameters were assessed for correlation with DCB (defined as progression free survival (PFS) > 6 months), PFS, and overall survival (OS), both alone and in the context of clinical and intratumoral parameters known to be predictive of survival in this disease state.\n\nPatients with DCB displayed a higher proportion of tumor infiltrating T lymphocytes (TIL) (n=24, Mann-Whitney p=0.047). Pre-treatment peripheral blood TCR clonality below the median was associated with improved PFS (n=29, log-rank p=0.048) and OS (n=29, log-rank p=0.011). Patients with DCB also demonstrated more substantial expansion of tumor-associated TCR clones in the peripheral blood 3 weeks after starting treatment (n=22, Mann-Whitney p=0.022). The combination of high pre-treatment peripheral blood TCR clonality with elevated PD-L1 IC staining in tumor tissue was strongly associated with poor clinical outcomes (n=10, HR (mean)=89.88, HR (median)=23.41, 95% CI (2.43, 506.94), p(HR>1)=0.0014). Marked variations in mutation loads were seen with different somatic variant calling methodologies, which in turn impacted associations with clinical outcomes. Missense mutation load, predicted neoantigen load and expressed neoantigen load did not demonstrate significant association with DCB (n=25, Mann-Whitney p=0.22, n=25, Mann-Whitney p=0.55, and n=25, Mann-Whitney p=0.29 respectively). Instead, we found evidence of time-varying effects of somatic mutation load on progression-free survival in this cohort (n=25, p=0.044). A limitation of our study is its small sample size (n=29), a subset of the patients treated on IMvigor 210 (NCT02108652). Given the number of exploratory analyses performed, we intend for these results to be hypothesis-generating.\n\nConclusionsThese results demonstrate the complex nature of immune response to checkpoint blockade and the compelling need for greater interrogation and data integration of both host and tumor factors. Incorporating these variables in prospective studies will facilitate identification and treatment of resistant patients.

cancer biology↗