Repertoire analyses reveal T cell antigen receptor sequence features that influence T cell fate

Lagattuta, Kaitlyn A.; Kang, Je-Won; Nathan, Aparna; Pauken, Kristen E.; Jonsson, Helena; Rao, Deepak A.; Sharpe, Arlene H.; Ishigaki, Kazuyoshi; Raychaudhuri, Soumya

doi:10.1038/s41590-022-01129-x

Cited by 41 publications

(51 citation statements)

References 46 publications

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“…Additionally, an association between autoreactive populations (Treg and IELp) and CDR3 amino acidic (AA) residue content, including the presence of cysteines within 2 positions of the CDR3 apex (cysteine index) and enrichment of hydrophobic AA doublets at positions 6 and 7 of the CDR3 (hydrophobic index), is reported 13,20 . Similar CDR3 properties are also reported to result in strong TCR-ligand interactions [21][22][23] . Finally, in contrast to NKT or MAIT cells, the repertoire of PNT IELps was determined to be polyclonal (fig.…”

Section: Resultssupporting

confidence: 71%

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Single-cell profiling identifies a spectrum of human unconventional intraepithelial T lineage cells

Billiet

Cock

Sanchez

et al. 2022

Preprint

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In the human thymus, a CD10+ PD-1+ TCRαβ+ differentiation pathway diverges from the conventional single positive T cell lineages at the early double positive stage. These cells are phenotypically and functionally similar to murine unconventional intraepithelial lymphocyte (uIEL) precursors. Here, the progeny of the human uIEL lineage was identified in antigen-inexperienced blood. The uIELs in thymus and peripheral blood share a transcriptomic profile, characterized by hallmark transcription factors (i.e. ZNF683 and IKZF2), and polyclonal TCR repertoire with autoreactive features, exhibiting a bias towards early TCR alpha chain rearrangements. Single-cell RNA sequencing confirmed a common developmental trajectory between the thymic and peripheral uIELs, and clearly delineated this unconventional lineage in peripheral blood. This population is phenotypically defined as CD3+ TCRαβ+ CD4- CCR7- CD26-. It contains CD10+ recent thymic emigrants, Helios+ KIR+ CD8+ Tregs and CD8αα+ T cells. Thus, the uIEL lineage represents a well-defined but heterogeneous, unconventional TCRαβ+ lineage mostly confined in human within the CD8 single positive T cells.

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Section: Resultssupporting

confidence: 71%

“…In line with this, the CDR3β repertoire exhibited higher interaction strength values (strength and volume parameters) compared to the PD-1 - population counterpart (fig. 2H) 21,22 . In contrast, polarity, a property associated with conventional T cells, was reduced in the CB PD-1 + population (fig.…”

Section: Resultsmentioning

confidence: 99%

Single-cell profiling identifies a spectrum of human unconventional intraepithelial T lineage cells

Billiet

Cock

Sanchez

et al. 2022

Preprint

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“…Hydrophobic residues (153,154) or Cysteine (154) on CDR3 are related to their selfreactivity. Hydrophobic CDRs enrichment in regulatory T cells is replicated by a logistic regression model with 606 T cell features to predict whether a cell becomes a regulatory T cell or not (155). Prediction of self-reactive T cells may play an important role in the diagnosis of autoimmune diseases in the future.…”

Section: Applications Of Repertoire Analysismentioning

confidence: 99%

Machine Learning Approaches to TCR Repertoire Analysis

et al. 2022

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Sparked by the development of genome sequencing technology, the quantity and quality of data handled in immunological research have been changing dramatically. Various data and database platforms are now driving the rapid progress of machine learning for immunological data analysis. Of various topics in immunology, T cell receptor repertoire analysis is one of the most important targets of machine learning for assessing the state and abnormalities of immune systems. In this paper, we review recent repertoire analysis methods based on machine learning and deep learning and discuss their prospects.

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“…Hence, Treg TCR repertoire is physiologically self-reactive (6)(7)(8). However, the process of negative selection is not 100% accurate.…”

Section: Introductionmentioning

confidence: 99%

“…Alternatively, some T cells with intermediate to high affinity to self-antigens may be positively selected and adopt a unique developmental fate by differentiating into regulatory T (Treg) cells. Hence, Treg TCR repertoire is physiologically self-reactive ( 6–8 ). However, the process of negative selection is not 100% accurate.…”

Section: Introductionmentioning

confidence: 99%

Loss of FOXP3 function causes expansion of two pools of autoreactive T cells in patients with IPEX syndrome

Borna

Lee

Lakshmanan

et al. 2022

Preprint

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The monogenic autoimmune disease Immunedysregulation polyendocrynopathy entheropathy X-linked syndrome (IPEX) has elucidated the essential function of the transcription factor FOXP3 and of thymic-derived regulatory T (Treg) cells in controlling autoimmunity. However, the presence of autoreactive T cells in IPEX remains undetermined, thus representing a crucial gap in understanding the origin of autoimmunity in a FOXP3 deficient immune system. Combining epigenetic analysis as a lineage marker of Treg identity and TCR sequencing to assess the self-reactive clones, we showed that IPEX patients have two pools of expanded autoreactive T cells. The first originates from the expansion of autoreactive effector T cells (Teff), likely due to loss of Treg suppressive function since it is absent in carrier mothers, in whom Treg cells are functional. The second pool originates, unexpectedly, from Treg cells which lose their phenotypic markers, including CD25 and FOXP3. We call these loss of identity Treg cells and show that they are i) suppressed by healthy donor Treg in a patient post hematopoietic transplantation despite low donor chimerism, and ii) not detectable in patients with Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED), a monogenic autoimmune disease of thymic origin. Moreover, we demonstrate that FOXP3 knock-out in Treg cells leads to increased Treg expansion and production of Th17 and Th2 cytokines, known to be increased in IPEX patients. These results suggest that the loss of identity Treg cells could directly contribute to immune dysregulation in IPEX. Collectively, we provide a better understanding of autoimmunity and novel ways to monitor the effects of Treg cell therapies in IPEX disease or other autoimmune diseases.

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Repertoire analyses reveal T cell antigen receptor sequence features that influence T cell fate

Cited by 41 publications

References 46 publications

Single-cell profiling identifies a spectrum of human unconventional intraepithelial T lineage cells

Single-cell profiling identifies a spectrum of human unconventional intraepithelial T lineage cells

Machine Learning Approaches to TCR Repertoire Analysis

Loss of FOXP3 function causes expansion of two pools of autoreactive T cells in patients with IPEX syndrome

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