Group of Structural Organization of T-cell Immunity

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Olga Britanova

MHC-II alleles shape the CDR3 repertoires of conventional and regulatory naïve CD4 T cells.

We investigated the generation of naïve CD4+ T cells in mice with different MHC-II genetic contexts and found out that the defective selection of CD4+ T cells on the j allelic variant of MHC-II (H2-Aj) was in agreement with the generation of less diverse and more public TCR repertoires. Furthermore, the selection on H2-Aj favored the development of T cells with a higher average number of hydrophobic and aromatic amino acid residues in the middle of TCR-CDR3 loops, which are mostly responsible for antigen recognition. Of note, the association of such amino acid residues in CDR3 and high affinity and cross-reactivity of the corresponding TCRs has been reported previously. We observed CD4+ regulatory T cells (Treg) with even more hydrophobic CDR3 loops, which were efficiently recruited into homeostatic proliferation on the periphery and even restored their number despite the defective thymic selection. This difference in the average number of hydrophobic and aromatic amino acids in the CDR3 middle part between conventional and naive Treg cells was more prominent in the H2-Aj genetic context.

We conducted functional in vitro experiments to measure the suppressive activity of Treg cells selected on distinct MHC-II allelic variants. Treg cells selected on H2-Aj demonstrated more effective suppression of proliferating autologous conventional CD4+ T cells. 

Publications

  1. Logunova NN, Kriukova VV, Shelyakin PV, Egorov ES, Pereverzeva A, Bozhanova NG, Shugay M, Shcherbinin DS, Pogorelyy MV, Merzlyak EM, Zubov VN, Meiler J, Chudakov DM, Apt AS, Britanova OV (2020). MHC-II alleles shape the CDR3 repertoires of conventional and regulatory naïve CD4 T cells. Proc Natl Acad Sci U S A 117 (24), 13659–13669

- two functionally distinct subpopulations of CD8 + memory stem cells described.

- a new approach developed to assess the clonal heterogeneity of tumor-infiltrating T-lymphocytes.

-  stably clonal T cell response was shown to be associated with a response to anti-PD1 immunotherapy.

- the T-cell repertoire of nickel-specific CD4 + T-lymphocytes was characterized.

- the repertoire of gamma-delta T lymphocytes involved in the antitumor response was investigated.

- a comparative analysis of the repertoire of follicular helper T-lymphocytes was carried out.

- a deep comparative study of methods for analyzing the repertoire of T-cell receptors was carried out.

Publications

  1. Galletti G, De Simone G, Mazza EMC, Puccio S, Mezzanotte C, Bi TM, Davydov AN, Metsger M, Scamardella E, Alvisi G, De Paoli F, Zanon V, Scarpa A, Camisa B, Colombo FS, Anselmo A, Peano C, Polletti S, Mavilio D, Gattinoni L, Boi SK, Youngblood BA, Jones RE, Baird DM, Gostick E, Llewellyn-Lacey S, Ladell K, Price DA, Chudakov DM, Newell EW, Casucci M, Lugli E (2020). Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans. Nat Immunol ,
  2. Yuzhakova DV, Volchkova LN, Pogorelyy MV, Serebrovskaya EO, Shagina IA, Bryushkova EA, Nakonechnaya TO, Izosimova AV, Zavyalova DS, Karabut MM, Izraelson M, Samoylenko IV, Zagainov VE, Chudakov DM, Zagaynova EV, Sharonov GV (2020). Measuring Intratumoral Heterogeneity of Immune Repertoires. Front Oncol 10, 512
  3. Zhigalova EA, Izosimova AI, Yuzhakova DV, Volchkova LN, Shagina IA, Turchaninova MA, Serebrovskaya EO, Zagaynova EV, Chudakov DM, Sharonov GV (2020). RNA-Seq-Based TCR Profiling Reveals Persistently Increased Intratumoral Clonality in Responders to Anti-PD-1 Therapy. Front Oncol 10, 385
  4. Aparicio-Soto M, Riedel F, Leddermann M, Bacher P, Scheffold A, Kuhl H, Timmermann B, Chudakov DM, Molin S, Worm M, Heine G, Thierse HJ, Luch A, Siewert K (2020). TCRs with segment TRAV9-2 or a CDR3 histidine are overrepresented among nickel-specific CD4+ T cells. Allergy 75 (10), 2574–2586
  5. Janssen A, Villacorta Hidalgo J, Beringer DX, van Dooremalen S, Fernando F, van Diest E, Terrizi AR, Bronsert P, Kock S, Schmitt-Gräff A, Werner M, Heise K, Follo M, Straetemans T, Sebestyen Z, Chudakov DM, Kasatskaya SA, Frenkel FE, Ravens S, Spierings E, Prinz I, Küppers R, Malkovsky M, Fisch P, Kuball J (2020). γδ T-cell Receptors Derived from Breast Cancer-Infiltrating T Lymphocytes Mediate Antitumor Reactivity. Cancer Immunol Res 8 (4), 530–543
  6. Brenna E, Davydov AN, Ladell K, McLaren JE, Bonaiuti P, Metsger M, Ramsden JD, Gilbert SC, Lambe T, Price DA, Campion SL, Chudakov DM, Borrow P, McMichael AJ (2020). CD4 T Follicular Helper Cells in Human Tonsils and Blood Are Clonally Convergent but Divergent from Non-Tfh CD4 Cells. Cell Rep 30 (1), 137–152.e5
  7. Barennes P, Quiniou V, Shugay M, Egorov ES, Davydov AN, Chudakov DM, Uddin I, Ismail M, Oakes T, Chain B, Eugster A, Kashofer K, Rainer PP, Darko S, Ransier A, Douek DC, Klatzmann D, Mariotti-Ferrandiz E (2020). Benchmarking of T cell receptor repertoire profiling methods reveals large systematic biases. Nat Biotechnol 39 (2), 236–245
  8. De Simone G, Mazza EMC, Cassotta A, Davydov AN, Kuka M, Zanon V, De Paoli F, Scamardella E, Metsger M, Roberto A, Pilipow K, Colombo FS, Tenedini E, Tagliafico E, Gattinoni L, Mavilio D, Peano C, Price DA, Singh SP, Farber JM, Serra V, Cucca F, Ferrari F, Orrù V, Fiorillo E, Iannacone M, Chudakov DM, Sallusto F, Lugli E (2019). CXCR3 Identifies Human Naive CD8 T Cells with Enhanced Effector Differentiation Potential. J Immunol 203 (12), 3179–3189

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

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