Conserved biophysical compatibility among the highly variable germline-encoded regions shapes TCR-MHC interactions
- National Institute of Allergy and Infectious Diseases, United States
Abstract
T cells are critically important components of the adaptive immune system primarily responsible for identifying and responding to pathogenic challenges. This recognition of pathogens is driven by the interaction between membrane-bound T cell receptors (TCRs) and antigenic peptides presented on major histocompatibility complex (MHC) molecules. The formation of the TCR-peptide-MHC complex (TCR-pMHC) involves interactions among germline-encoded and hypervariable amino acids. Germline-encoded and hypervariable regions can form contacts critical for complex formation, but only interactions between germline-encoded contacts are likely to be shared across many of all the possible productive TCR-pMHC complexes. Despite this, experimental investigation of these interactions have focused on only a small fraction of the possible interaction space. To address this, we analyzed every possible germline-encoded TCR-MHC contact in humans, thereby generating the first comprehensive characterization of these largely antigen-independent interactions. Our computational analysis suggests that germline-encoded TCR-MHC interactions that are conserved at the sequence level are rare due to the high amino acid diversity of the TCR CDR1 and CDR2 loops, and that such conservation is unlikely to dominate the dynamic protein-protein binding interface. Instead, we propose that binding properties such as the docking orientation are defined by regions of biophysical compatibility between these loops and the MHC surface.
Data availability
All data and code used for the analysis in this manuscript are freely available online with no restrictions. All input FASTA sequences and code needed to recreate the analysis can be found via the AIMS GitHub page: github.com/ctboughter/AIMS. Specific analysis for structural comparisons between interaction potentials and TCR-pMHC complexes are found via a separate repository, called PRESTO, also hosted on GitHub: github.com/ctboughter/PRESTO. Due to the significant time required to calculate the interaction scores calculated via AIMS, the calculated scores can be found on Zenodo at the following DOI: 10.5281/zenodo.7023681. In case of future updates to either AIMS or PRESTO, the specific versions used for this manuscript are also hosted on Zenodo, as AIMS v0.8 [DOI: 10.5281/zenodo.7025972] and PRESTO v0.2 [DOI: 10.5281/zenodo.7025652].
Article and author information
Author details
Christopher T Boughter
Martin Meier-Schellersheim
Funding
National Institutes of Health
- Christopher T Boughter
- Martin Meier-Schellersheim
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Metrics
-
- 835
- views
-
- 109
- downloads
-
- 1
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Conserved biophysical compatibility among the highly variable germline-encoded regions shapes TCR-MHC interactions
eLife 12:e90681.
https://doi.org/10.7554/eLife.90681
Further reading
-
- Immunology and Inflammation
miRNAs constitute fine-tuners of gene expression and are implicated in a variety of diseases spanning from inflammation to cancer. miRNA expression is deregulated in rheumatoid arthritis (RA); however, their specific role in key arthritogenic cells such as the synovial fibroblast (SF) remains elusive. Previous studies have shown that Mir221/222 expression is upregulated in RA SFs. Here, we demonstrate that TNF and IL-1β but not IFN-γ activated Mir221/222 gene expression in murine SFs. SF-specific overexpression of Mir221/222 in huTNFtg mice led to further expansion of SFs and disease exacerbation, while its total ablation led to reduced SF expansion and attenuated disease. Mir221/222 overexpression altered the SF transcriptional profile igniting pathways involved in cell cycle and ECM (extracellular matrix) regulation. Validation of targets of Mir221/222 revealed cell cycle inhibitors Cdkn1b and Cdkn1c, as well as the epigenetic regulator Smarca1. Single-cell ATAC-seq data analysis revealed increased Mir221/222 gene activity in pathogenic SF subclusters and transcriptional regulation by Rela, Relb, Junb, Bach1, and Nfe2l2. Our results establish an SF-specific pathogenic role of Mir221/222 in arthritis and suggest that its therapeutic targeting in specific subpopulations could lead to novel fibroblast-targeted therapies.
-
- Immunology and Inflammation
Allergic contact dermatitis (ACD), a prevalent inflammatory skin disease, is elicited upon repeated skin contact with protein-reactive chemicals through a complex and poorly characterized cellular network between immune cells and skin resident cells. Here, single-cell transcriptomic analysis of the murine hapten-elicited model of ACD reveals that upon elicitation of ACD, infiltrated CD4+ or CD8+ lymphocytes were primarily the IFNγ-producing type 1 central memory phenotype. In contrast, type 2 cytokines (IL4 and IL13) were dominantly expressed by basophils, IL17A was primarily expressed by δγ T cells, and IL1β was identified as the primary cytokine expressed by activated neutrophils/monocytes and macrophages. Furthermore, analysis of skin resident cells identified a sub-cluster of dermal fibroblasts with preadipocyte signature as a prominent target for IFNγ+ lymphocytes and dermal source for key T cell chemokines CXCL9/10. IFNγ treatment shifted dermal fibroblasts from collagen-producing to CXCL9/10-producing, which promoted T cell polarization toward the type-1 phenotype through a CXCR3-dependent mechanism. Furthermore, targeted deletion of Ifngr1 in dermal fibroblasts in mice reduced Cxcl9/10 expression, dermal infiltration of CD8+ T cell, and alleviated ACD inflammation in mice. Finally, we showed that IFNγ+ CD8+ T cells and CXCL10-producing dermal fibroblasts co-enriched in the dermis of human ACD skin. Together, our results define the cell type-specific immune responses in ACD, and recognize an indispensable role of dermal fibroblasts in shaping the development of type-1 skin inflammation through the IFNGR-CXCR3 signaling circuit during ACD pathogenesis.
