A5101632050- vaccines and immunoinformatics approaches
- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- SARS-CoV-2 and COVID-19 Research
- CAR-T cell therapy research
- HIV Research and Treatment
- COVID-19 Clinical Research Studies
- Monoclonal and Polyclonal Antibodies Research
- Reproductive System and Pregnancy
- Cancer Immunotherapy and Biomarkers
- COVID-19 epidemiological studies
- Receptor Mechanisms and Signaling
- Aquaculture disease management and microbiota
- Chemokine receptors and signaling
- MicroRNA in disease regulation
- Nuclear Receptors and Signaling
- Immune responses and vaccinations
- RNA regulation and disease
- Diabetes and associated disorders
- Phagocytosis and Immune Regulation
- Zebrafish Biomedical Research Applications
- Viral Infections and Outbreaks Research
Koch Institute for Integrative Cancer Research At MIT
2021-2024
Howard Hughes Medical Institute
2021-2024
Ragon Institute of MGH, MIT and Harvard
2020-2024
Allen Institute
2021-2023
Massachusetts Institute of Technology
2020-2023
Indian Institute of Toxicology Research
2023
University of Notre Dame
2018-2022
IIT@MIT
2022
Massachusetts General Hospital
2020
Harvard University
2020
Abstract Cytotoxic-T-lymphocyte (CTL) mediated control of HIV-1 is enhanced by targeting highly networked epitopes in complex with human-leukocyte-antigen-class-I (HLA-I). However, the extent to which presenting HLA allele contributes this process unknown. Here we examine CTL response QW9, a epitope presented disease-protective HLA-B57 and disease-neutral HLA-B53. Despite robust QW9 persons expressing either allele, T cell receptor (TCR) cross-recognition naturally occurring variant QW9_S3T...
Abstract HLA-E is a non-classical class I MHC protein involved in innate and adaptive immune recognition. While recent studies have shown can present diverse peptides to NK cells T cells, the repertoire recognized by CD94/NKG2x has remained poorly defined, with only limited number of peptide ligands identified. Here we screen yeast-displayed library context identify 500 high-confidence unique that bind both CD94/NKG2A or CD94/NKG2C. Utilizing sequences identified via yeast display...
Humoral responses in COVID-19 disease are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined postmortem thoracic lymph nodes and spleens acute SARS-CoV-2 infection observed absence germinal centers, a striking reduction Bcl-6+ center B cells but preservation AID+ cells. Absence centers correlated an early specific block Bcl-6+TFH cell differentiation together increase T-bet+TH1 aberrant extra-follicular TNF-a...
Defining factors that govern CD8+ T cell immunodominance is critical for the rational design of vaccines viral pathogens. Here, we assess contribution human leukocyte antigen (HLA) class-I-peptide stability 186 optimal HIV epitopes across 18 HLA alleles using transporter associated with processing (TAP)-deficient mono-allelic HLA-expressing lines. We find immunodominant increase surface stabilization class-I molecules in comparison to subdominant epitopes. also strongly correlated overall...
Significance The strength of peptide binding to class I MHC proteins is a correlate immunogenicity. However, many peptides interest, including shared tumor antigens, bind weakly and are poorly immunogenic. Considerable effort has been spent generating stronger-binding variants these, with the goal using them as vaccines elicit responses against unmodified peptides. We show that common modifications used improve can unpredictably alter T cell recognition. alterations arise from structurally...
Cancer immunotherapies, in particular checkpoint blockade immunotherapy (CBT), can induce control of cancer growth, with a fraction patients experiencing durable responses. However, the majority currently do not respond to CBT and molecular determinants resistance have been fully elucidated. Mounting clinical evidence suggests that clonal status neoantigens (NeoAg) impacts anti-tumor T cell response. High intratumor heterogeneity (ITH), where NeoAgs are expressed subclonally, is correlated...
Abstract Recognition of antigenic peptides bound to major histocompatibility complex (MHC) proteins by αβ T cell receptors (TCRs) is a hallmark mediated immunity. Recent data suggest that variations in TCR binding geometry may influence signaling, which could help explain outliers relationships between physical parameters such as TCR‐pMHC affinity and function. Traditionally, has been described with simple descriptors the crossing angle, quantifies what become known TCR's diagonal mode....
Abstract MHC restriction, which describes the binding of TCRs from CD4 + T cells to class II proteins and CD8 I proteins, is a hallmark immunology. Seemingly rare that break this paradigm exist, but mechanistic insight into their behavior lacking. TIL1383I prototypical class-mismatched TCR, cloned cell recognizing tyrosinase tumor antigen presented by HLA-A2 in fully functional manner. Here we find binds target with highly atypical geometry. Despite unorthodox binding, TCR signaling,...
While immune checkpoint blockade results in durable responses for some patients, many others have not experienced such benefits. These treatments rely upon reinvigorating specific T cell-antigen interactions. However, it is often unknown what antigens are being recognized by cells or how to potently induce antigen-specific a broadly applicable manner. Here, we characterized the CD8 + cell response murine model of melanoma following combination immunotherapy determine basis tumor recognition....
T cell receptors (TCRs) orchestrate cellular immunity by recognizing peptides presented a range of major histocompatibility complex (MHC) proteins. Naturally occurring TCRs bind the composite peptide/MHC surface, that are structurally and chemically compatible with TCR binding site. Here we describe molecularly evolved variant binds human class I MHC protein HLA-A2 independent bound peptide, achieved drastic perturbation geometry places molecule far from peptide groove. This unique is...
Abstract HLA-E is a non-classical class I MHC protein involved in innate and adaptive immune recognition. While recent studies have shown can present diverse peptides to NK cells T cells, the receptor peptide repertoire has remained poorly defined, with only limited number of ligands identified. Here we screen yeast-displayed library context identify 500 high-confidence unique that bind both CD94/NKG2A or CD94/NKG2C. Utilizing sequences identified via yeast display selections, train...
Abstract Polymorphisms in human leukocyte antigen ( HLA ) genes strongly influence outcomes to HIV infection. However, the underlying mechanisms by which certain alleles mediate protection is not well understood. Here we systematically investigate residues within class I molecules (at positions 67, 70, 97 and 156) that have been demonstrated genetic studies explain observed variation of on Through a detailed assessment protective HLA-B*5701 allele, find each these has distinct effects either...
Using adoptive cell transfer to reintroduce engineered T cells into patients is an exciting new form of cancer immunotherapy. play a central role in adaptive immunity by eliminating virus‐infected and tumor cells. receptors (TCRs) facilitate this recognizing antigenic peptides presented major histocompatibility complexes (MHCs), triggering immune response. While TCRs gene‐modified can be used for anti‐tumor clinical responses, trials have shown adverse effects attributable off‐target...
Abstract T cell therapy is an exciting form of cancer immunotherapy in which cells are engineered to target specific tumor antigens. We employed a structure-guided design approach with the goal engineering safer and more effective variant TIL1383I receptor (TCR) currently under study clinical trials for malignant melanoma. Using our unpublished structure we process designing panel TCR variants identifying candidates that improve “focus” towards tyrosinase antigen presented on MHC class I...
Abstract While immune checkpoint blockade results in durable responses for some patients, many others have not experienced such benefits. These treatments rely upon reinvigorating specific T cell-antigen interactions. However, it is often unknown what antigens are being recognized by cells or how to potently induce antigen-specific a broadly applicable manner. Here, we characterized the CD8 + cell response murine model of melanoma following combination immunotherapy determine basis tumor...