Functionally specialized human CD4+ T cell subsets express physicochemically distinct TCRs
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Federation
- Cardiff University School of Medicine, United Kingdom
- Central European Institute of Technology, Czech Republic
- Lomonosov Moscow State University, Russian Federation
Abstract
The organizational integrity of the adaptive immune system is determined by functionally discrete subsets of CD4+ T cells, but it has remained unclear to what extent lineage choice is influenced by clonotypically expressed T cell receptors (TCRs). To address this issue, we used a high-throughput approach to profile the ab TCR repertoires of human naive and effector/memory CD4+ T cell subsets, irrespective of antigen specificity. Highly conserved physicochemical and recombinatorial features were encoded on a subset-specific basis in the effector/memory compartment. Clonal tracking further identified forbidden and permitted transition pathways, mapping effector/memory subsets related by interconversion or ontogeny. Public sequences were largely confined to particular effector/memory subsets, including regulatory T cells (Tregs), which also displayed hardwired repertoire features in the naive compartment. Accordingly, these cumulative repertoire portraits establish a link between clonotype fate decisions in the complex world of CD4+ T cells and the intrinsic properties of somatically rearranged TCRs.
Data availability
All extracted repertoires and metadata are deposited in Figshare: https://figshare.com/s/2145b1b16c6854445af7 and https://figshare.com/s/84ec5f412356afb0536d.
-
Human effector/memory CD4 T cell subsets: deep TCR profiling.NCBI Gene Expression Omnibus, GSE158848.
Article and author information
Author details
Elena K Matveishina
Dmitriy M Chudakov
Funding
Ministry of Science and Higher Eductaion of Russian Federation (075-15-2019-1789)
- Dmitriy M Chudakov
Wellcome Trust (100326/Z/12/Z)
- David A Price
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Ethical approval was granted by the institutional review committees at Cardiff University School of Medicine (reference number 16/55) and the Pirogov Russian National Research Medical University (protocol number 2017/52) and all donors provided informed consent for their participation in the study.
Copyright
© 2020, Kasatskaya et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Download links
Further reading
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
The members of the Mycobacterium tuberculosis complex (MTBC) causing human tuberculosis comprise 10 phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human in vitro granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets—a phenotype associated with dormancy—that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B, and TNF. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.
-
- Immunology and Inflammation
Macrophages control intracellular pathogens like Salmonella by using two caspase enzymes at different times during infection.
