Department of Genomics of Adaptive Immunity

All publications (show selected)

Dmitriy Chudakov

Study of the role of tumor-infiltrating B-lymphocytes

Laboratory of immunosequencing methods

- For the first time, the association of the isotype composition of antibodies and B-cell receptors in the tumor environment and the prognosis of patient survival associated with the presence of certain driver mutations is shown.

- The role of tumor-infiltrating B-lymphocytes was first systemically characterized through the prism of the analysis of repertoires of antibodies and B-cell receptors.

Joint work with Privolzhsky Research Medical University.

 

Publications:

1) Isaeva OI, Sharonov GV, Serebrovskaya EO, Turchaninova MA, Zaretsky AR, Shugay M, Chudakov DM (2019). Intratumoral immunoglobulin isotypes predict survival in lung adenocarcinoma subtypes. J Immunother Cancer 7 (1), 279

2) Sharonov GV, Serebrovskaya EO, Yuzhakova DV, Britanova OV, Chudakov DM (2020). B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nature Rev. Immunology, in press.

 

A new approach to the functional analysis of sequencing data for T-lymphocyte repertoires

Laboratory of immunosequencing methods,  Group of Immunosequencing Algorithms,  Laboratory of comparative and functional genomics

In order to extract clinically relevant information from large high-throughput sequencing of TCR repertoires we create a new statistical approach - Antigen-specific Lymphocyte Identification by Clustering of Expanded sequences (ALICE) /fig a/. We applied our algorithm to distinguish naïve from the effector memory cells in available TCR beta repertoires /fig b/, to identify reactive T-cell clones in mixed lymphocyte reaction (MLR) assay /fig c, d/, to fractionate TCR repertoires of patients with autoimmune disease or ones being under cancer immunotherapy, or subject to an acute viral infection. In summary, implementation of ALICE facilitate the identification of TCR variants associated with diseases and conditions, which can be used for diagnostics and rational vaccine design.

Formation of the CD4+ and regulatory CD4+ T cell receptor repertoire.

Group of Structural Organization of T-cell Immunity

We studied how different allelic variants of MHC class II shape the TCR repertoires of naive helper and regulatory CD4 + T lymphocytes in two mouse lines. We reveal profound differences in the diversity, convergence, and physicochemical properties of their antigen-interacting regions TCR CDR3 among repertoires of these mouse strains. At the population level, such differences are likely to influence individual susceptibility to infections and autoimmunity.

In our other study, we found that CD4 + lymphocytes with the T memory-like phenotype have been found in the umbilical cord blood and in the embryonic intestine. A rare population of memory CD4+ T cells produce proinflammatory spectrum of cytokines and is characterized by a highly similar TCR repertoires of these cells between different donors, which may indicate the formation of memory in response to similar foreign antigens.

Publications

  1. Li N, van Unen V, Abdelaal T, Guo N, Kasatskaya SA, Ladell K, McLaren JE, Egorov ES, Izraelson M, Chuva de Sousa Lopes SM, Höllt T, Britanova OV, Eggermont J, de Miranda NFCC, Chudakov DM, Price DA, Lelieveldt BPF, Koning F (2019). Memory CD4 T cells are generated in the human fetal intestine. Nat Immunol 20 (3), 301–312

Clonal profiling of T cell response to antiviral vaccination

Laboratory of comparative and functional genomics

T cell receptor (TCR) repertoire data contain information about infections that could be used in disease diagnostics and vaccine development, but extracting that information remains a major challenge. Here we developed an experimental approach with a statistical framework to detect TCR clone proliferation and contraction from longitudinal repertoire data. We applied this framework to data from three pairs of identical twins immunized with the yellow fever vaccine. We identified 600 to 1,700 responding TCRs in each donor and validated them using three independent assays. While the responding TCRs were mostly private, albeit with higher overlap between twins, they could be well-predicted using a classifier based on sequence similarity. Our method can also be applied to samples obtained postinfection, making it suitable for systematic discovery of new infection-specific TCRs in the clinic.

Photoswitchable red fluorescent proteins for nanoscopy of live cells

Laboratory of immunosequencing methods,  Laboratory of genetically encoded molecular tools

We developed new reversibly photoswitchable red fluorescent proteins based on FusionRed. These proteins, rsFusionRed1, 2 and 3, can be switched OFF and ON and by orange and green light, respectively. This photoswitching behavior allows to avoid illumination by phototoxic violet and blue light, which is commonly used for other photoswitchable proteins. Due to high brightness, high photostability, rapid photoswitching and low phototoxic excitation wavelengths rsFusionReds represent excellent tags for nanoscale imaging of living cells.

Publications

  1. Pennacchietti F, Serebrovskaya EO, Faro AR, Shemyakina II, Bozhanova NG, Kotlobay AA, Gurskaya NG, Bodén A, Dreier J, Chudakov DM, Lukyanov KA, Verkhusha VV, Mishin AS, Testa I (2018). Fast reversibly photoswitching red fluorescent proteins for live-cell RESOLFT nanoscopy. Nat Methods 15 (8), 601–604

T cell immune response to the flu vaccination

Laboratory of comparative and functional genomics

Deep quantitative T cell receptors profiling of peripheral lymphocytes have been performed to investigate T cell impact on the human immune response to the trivalent subunit influenza vaccine. Besides the fact that the flu vaccination does not lead to a significant rebuilding of T-lymphocytes repertoire, we founded small oligoclonal subpopulation bearing T cell memory phenotype. The subpopulation appears at 45th day after vaccine administration and then decreases its proportion of T cell clones in the repertoire. These “new memory” T cell clones suggest a potential for recruitment of a limited number of new T cells after each seasonal influenza vaccination.

Investigation of T-cell receptors and antibody repertoires in health and disease