Biology subjects

Davydov, A. N.

Publications and source records attributed to Davydov, A. N..

3 recordsLinked to original sources

bioRxiv2024

Tracking antigen-specific T cell response to cancer immunotherapy

In each human or model animal, T cell receptor (TCR) of each effector/memory T cell clone recognizes from one to several cognate peptide-MHC complexes (pMHC). Limited knowledge on TCR repertoire specificities restricts our capacity to rationally interpret this information, both diagnostically and in preclinical research. Here we 1) develop cost-efficient wet lab and computational pipeline to identify mouse TCRs specific to particular peptides, 2) produce dataset of helper T cells (Th) TCR beta CDR3s specific to B16 melanoma neoantigens in the I-Ab pMHCII context, available in VDJdb, and 3) apply this dataset to track tumor-specific T cell response to the CTLA4 blocking immunotherapy on orthotopic B16 melanoma model. We show that tumor promotes clonally independent Tregs carrying tumor-specific TCRs characteristic for Th cells. We further show that CTLA4 blockade promotes Th clonal expansion and induces general, non-tumor-specific Th-to-Treg plasticity. Altogether, we provide a universal pipeline for the investigation of mouse T cell responses at the antigen-specific level, facilitating development and validation of immunotherapeutic and vaccination approaches.

immunology↗

bioRxiv2019

CD4+ T follicular helper (Tfh) cells in human tonsil and blood are clonally convergent, but divergent from non-Tfh CD4+ cells

T follicular helper (Tfh) cells are fundamental for B cell selection and antibody maturation in germinal centers. Circulating Tfh (cTfh) cells constitute a minor proportion of the CD4+ T cells in peripheral blood, but their clonotypic relationship to Tfh populations resident in lymph nodes and the extent to which they differ from non-Tfh CD4+ cells has been unclear. Using donor-matched blood and tonsil samples we investigated T cell receptor (TCR) sharing between tonsillar Tfh cells and peripheral Tfh and non-Tfh cell populations. TCR transcript sequencing revealed considerable clonal overlap between peripheral and tonsillar Tfh cell subsets as well as a clear distinction between Tfh and non-Tfh cells. Furthermore, influenza-specific cTfh cell clones derived from blood could be found in the repertoire of tonsillar Tfh cells. Therefore, human blood samples can be used to gain insight into the specificity of Tfh responses occurring in lymphoid tissues, provided cTfh subsets are studied.

immunology↗

bioRxiv2018

T cell immunity does not age in a long-lived rodent species

Numerous studies have demonstrated that the percentage of naive T cells and diversity of T cell receptor (TCR) repertoire decrease with age, with some findings likewise suggesting that increased repertoire diversity may be associated with longer lifespan and healthy aging. In this work, we have analyzed peripheral TCR diversity from humans, mice, and blind mole-rats (Spalax spp.)--long-lived, hypoxia- and cancer-tolerant rodents. We employed a quantitative approach to TCR repertoire profiling based on 5RACE with unique molecular identifiers (UMI) to achieve accurate comparison of repertoire diversity, which also required development of specific wet lab protocol and TCR gene reference for Spalax. Our direct comparison reveals a striking phenomenon. Whereas TCR diversity of mice and humans decreases with age, resulting primarily from the shrinkage of the naive T cell pool, Spalax TCR diversity remains stable even for the animals that reach extreme old age (15-17 years). This indicates that T cell immunity does not meaningfully age in long-lived rodents, at least in terms of the classical understanding of immunosenescence, which is associated with the accumulation of large numbers of memory clones. We suggest that the extraordinary longevity of Spalax may be attributable at least in part to the distinctive organization of their T cell immunity. Our findings should therefore encourage a close re-examination of the contribution of immunosenescence to life span in mammals.

immunology↗