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How researchers around the world are
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Infectious Disease_outline-stroke

Infectious Disease

Diagnostic differentiation of Zika and dengue virus exposure by analyzing T cell receptor sequences from peripheral blood of infected HLA-A2 transgenic mice 

Hassert M, Pinto AK, et al., PLoS Neglected Tropical Diseases  2020
St. Louis University, St. Louis, MO 

Diagnostic differentiation between Zika virus (ZIKV) or Dengue (DENV) infection with serological techniques is a substantial challenge because cross-reactive antibodies are generated at extremely high frequency...This group hypothesized that T-cell receptor sequencing (TCR sequencing coupled to a statistical classifier would enable the creation of a T-cell-based differentiating diagnostic for these viruses. HLA-A2 transgenic mice were infected with either ZIKV or DENV2, re-exposed 14 days later, and blood was collected at days 0, 8, and 18 post-infection for sequencing with the immunoSEQ® Mouse TCRB Assay. Serum samples from day 0 and day 18 showed no measurable difference in quantity of ZIKV reactive antibodies between sera from ZIKV or DENV2 infection. Instead, to identify TCRB clones specifically associated to either virus, they enumerated number of samples each clone was present in, compared those to clonotypes present prior to challenge, and used Fisher's Exact Test to generate a list of TCRs indicative of ZIKV or DENV. They went on to successfully develop diagnostic classifiers by determining ratio of ZIKV-associated or DENV2-associated TCRs relative to total number of unique TCRB clones present in each sample. With this approach their classifier was able to distinguish ZIKV infection from DENV2 infection with 97% accuracy. This classifier was accurate even 18 months after initial infection, suggesting that T cell-based tests could prove useful for differentiation of viral infections.

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Characterization of ascites- and tumor-infiltrating T cells reveals distinct repertoires and a beneficial role in ovarian cancer

Foord E, Uhlin M, et al., Science Translational Medicine 2021
Karolinska Institutet, Stockholm, Sweden  

Tumor infiltrating CD3+ and CD8+ A/B T cells have been associated with favorable outcomes in epithelial ovarian cancer (EOC) patients, but the role of G/D T cells has not yet been explored...This study explored G/D T-cell composition and repertoire properties using flow cytometry and TCRG chain sequencing using the immunoSEQ® TCRG Assay. Peripheral blood, ascites, and tumor samples from 8 EOC patients were assessed on the basis of TCRG repertoire diversity, gene usage, CDR3 length distributions, and clonotype overlap, in addition to several other metrics. Among numerous findings, TCRG repertoires from tumor samples were more diverse (lower clonality) and less similar to peripheral blood and ascites in terms of repertoire overlap (as determined by Morisita Overlap Index). Sequence clustering by TCRG CDR3 length found the most common CDR3 length from blood and ascites (14 AA) contained motifs that favored phosphorylated antigen recognition, suggestive of an innate-like immune response. In contrast, the most common CDR3 length in tumor (12 AA) contained more distinct sequences suggesting an adaptive immune response. Additional phenotyping experiments revealed potential biomarkers for therapeutic intervention, including CD39, which may act to downregulate the G/D T-cell response to EOC. Overall, this study provides evidence for the multimodal immune response of G/D T cells with potential therapeutic applications in EOC and serves as a reference point for additional research.

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Human-engineered Treg-like cells suppress FOXP3-deficient T cells but preserve adaptive immune responses in vivo  

Sato Y, Baccheta R, et al., Clinical & Translational Immunology 2020 
Stanford University School of Medicine, Stanford, CA 

Genetic defects in FOXP3, a critical transcription factor for Treg function, can cause the autoimmune disease IPEX (immune dysregulation polyendocrinopathy, enteropathy, X-linked) syndrome. There is a high unmet need for effective therapies targeting IPEX syndrome current treatment options, such as immunosuppression or HSCT, have a number of associated side effects. This group previously demonstrated that Treg-like cells can be engineered via lentiviral transduction of FOXP3 constructs into IPEX patient-derived CD4+ T cells. This paper characterizes these Treg-like cells (CD4LVFOXP3) with transcriptional analysis, the immunoSEQ® TCRB Assay, and provides functional assessments in humanized mouse models. The in vitro conversion of human CD4+ T cells into Treg-like cells was confirmed to upregulate Treg-related genes, protect humanized mice from xeno-GvHD, and prevent proliferation of pathogenic T cells in FOXP3-deficient IPEX-like humanized mice. In addition, the immunoSEQ Human TCRB Assay was used to show that TCR diversity was preserved in cells manipulated in vitro, as clonality, CDR3 lengths, and V gene usages were not significantly altered. These data were taken to suggest that CD4LVFOXP3 should be further evaluated in clinical trials for the management of autoimmune disorders caused by FOXP3-deficiency. 

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The TCR repertoire of α‐synuclein‐specific T cells in Parkinson's disease is surprisingly diverse

Singhania A, Arlehamm CSL, et al., Scientific Reports 2021
La Jolla Institute for Immunology

The neuronal protein-synuclein (-syn) has been linked genetically and neuropathologically to Parkinson's disease (PD). Recent studies have shown PD patients possess -syn-specific T cells, suggesting an autoimmune component to disease progression. ..These -syn-specific T cells were detectable at higher levels pre-diagnosis and may therefore be an attractive therapeutic target or biomarker for early detection. Here, the authors characterized and compared the -syn- and pertussis (PT)-specific T-cell repertoire in 6 PD patients using the immunoSEQ® TCRB Assay. PT- and -syn-specific TCRs were determined from antigen-stimulation assays using PD patient PBMCs and PT/-syn antigen pools. The number of stimulation-specific clonotypes identified for each antigen pool was similar, a result the authors described as "surprising" since self-antigens tend to produce a less-diverse T-cell response compared to foreign antigens. However, the aggregate productive frequencies of the -syn-specific T cells were significantly lower than for PT-specific T cells, which the authors speculate could be a property of self- versus foreign-antigen immune response. While no public -syn-specific TCRs were found, additional studies using larger cohorts would be necessary to determine potential HLA-specificities of the -syn-specific T-cell response.

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T cell repertoire analysis suggest a prominent bystander response in human cardiac allograft vasculopathy

Habal MV, Zorn E, et al., American Journal of Transplantation 2020
Columbia University Irving Medical Center

Cardiac allograft vasculopathy (CAV) remains a formidable barrier to successful long-term outcomes in heart transplantation. Recently, this same research group investigated the dynamics of the B-cell receptor (BCR) repertoire in the context of CAV in an effort to improve heart transplant outcomes (Moore et al., Am. J. Transplant. 2020). Using the immunoSEQ® IGH Assay, they reported significant BCR clonal expansion and increased somatic hypermutation (SHM) counts within CAV patient allografts may contribute to the pathophysiology of CAV. In the present study, they extended the analysis to the T-cell receptor (TCR) repertoire of CAV patient allografts. Using the immunoSEQ TCRB and IGH Assays, they characterized and compared the TCR and BCR repertoires in the coronary artery, endomyocardium, and peripheral blood at the time of retransplant in 4 cases of CAV. Among several findings, they reported lower TCR clonality in all grafts compared to blood, as well as extensive repertoire overlap between graft and blood TCRs. In contrast, they found higher BCR clonality in 3/4 grafts compared to blood, accompanied by minimal repertoire overlap between graft and blood TCRs. These data point to an active local intragraft bystander T-cell response in CAV, and the authors suggest these bystander T cells may be a potential therapeutic target.

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Diagnosis and Tracking of SARS-CoV-2 Infection By T-Cell Receptor Sequencing

Gittelman RM, Crisanti A, et., preprint Medrxiv 2021.
Adapitve Biotechnologies, Seattle WA

In viral diseases T cells exert a prominent role in orchestrating the adaptive immune response and yet a comprehensive assessment of the T-cell repertoire, compared and contrasted with antibody response, after severe acute respiratory syndrome coronavirus 2 . (SARS-CoV-2) infection is currently lacking. A prior population-scale study of the municipality of Vo', Italy, conducted after the initial SARS-CoV-2 outbreak uncovered a high frequency of asymptomatic infected individuals and their role in transmission in this town. Two months later, we sampled the same population's T-cell receptor (TCR) repertoire structure in terms of both diversity (breadth) and frequency (depth) to SARS-CoV-2 antigens to identify associations with both humoral response and protection. For this purpose, we analyzed TCR and antibody signatures from over 2,200 individuals, including 76 PCR-confirmed SARS-CoV-2 cases (25 asymptomatic, 42 symptomatic, 9 hospitalized). We found that 97.4% (74/76) of PCR confirmed cases had elevated levels of TCRs specific for SARS-CoV-2 antigens. The depth and breadth of the TCR repertoires were both positively associated with neutralizing antibody titers; helper CD4+ T cells directed towards viral antigens from spike protein were a primary factor in this correlation. Higher clonal depth of the T-cell response to the virus was also significantly associated with more severe disease course. A total of 40 additional suspected infections were identified based on T-cell response from the subjects without confirmatory PCR tests, mostly among those reporting symptoms or having household exposure to a PCR-confirmed infection. The authors suggest that, taken together, these results establish that T cells are a sensitive, reliable, and persistent measure of past SARS-CoV-2 infection that are differentially activated depending on disease morbidity. Research and or collaboration financially supported by Adaptive Biotechnologies.

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