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The T cell receptor (TCR) endows T cells with antigen specificity and is central to nearly all aspects of T cell function. Each naïve T cell has a unique TCR sequence that is stably maintained during cell division. In this way, the TCR serves as a molecular barcode that tracks processes such as migration, differentiation, and proliferation of T cells. Recent technological advances have enabled sequencing of the TCR from single cells alongside deep molecular phenotypes on an unprecedented scale. In this review, we discuss strengths and limitations of TCR sequences as molecular barcodes and their application to study immune responses following Programmed Death-1 (PD-1) blockade in cancer. Additionally, we consider applications of TCR data beyond use as a barcode. The T cell receptor (TCR) can act as a molecular barcode in mice and humans to track T cells with clonal-relatedness through processes such as migration, differentiation, and proliferation. The TCR sequence provides a means to enrich T cells of interest in diverse types of cancer and some types of autoimmunity. Using the TCR as a barcode in cancer has been useful for identifying mechanisms of Programmed Death-1 (PD-1) blockade-based immunotherapy and features associated with clinical responses in diverse cancer types. Using the TCR sequence to identify T cell populations of interest is currently limited by our inability to confidently infer antigen-specificity from the TCR sequence. Beyond acting as a molecular-identity barcode, the TCR sequence consists of a set of features that can inform T cell fate and function. [ABSTRACT FROM AUTHOR]

• Anatomical and physiological niches had significant influence on the distribution of an organism's TCR repertoire. • T cell receptor repertoire diversity and clonal expansion varied by anatomical location. • Small intestinal CD4 + T cell repertoire harbored highly expanded public clonotypes. T cells mediate adaptive immunity in diverse anatomic compartments through recognition of specific antigens via unique T cell receptor (TCR) structures. However, little is known about the spatial distribution of an organism's TCR repertoire. Here, using high-throughput TCR sequencing (TCRseq), we investigated the TCR repertoires of sixteen tissues in healthy C57B/L6 mice. We found that TCR repertoires generally classified into three categories (lymph nodes, non-lymph node tissues and small intestine) based on sequence similarity. Clonal distribution and diversity analyses showed that small intestine compartment had a more skewed repertoire as compared to lymph nodes and non-lymph node tissues. However, analysis of TRBV and TRBJ gene usage across tissue compartments, as well as comparison of CDR3 length distributions, showed no significant tissue-dependent differences. Interestingly, analysis of clonotype sharing between mice showed that although non-redundant public clonotypes were found more easily in lymph nodes, small intestinal CD4 + T cells harbored more abundant public clonotypes. These findings under healthy physiological conditions offer an important reference dataset, which may contribute to our ability to better manipulate T cell responses against infection and vaccination. [ABSTRACT FROM AUTHOR]

• TCR diversity increased in biologic-treated AS patients with better improvement. • Higher difference of contracted minus expanded TCRs related to better improvement. • IL-23 level positively correlated with TCR diversity in AS patients. • AS-associated TCRs contracted in biologic-treated patients with better improvement. Ankylosing spondylitis (AS) is a chronic inflammatory autoimmune disease in which T-cell immune responses play important roles. AS has been characterized by altered T-cell receptor (TCR) repertoire profiles, which are thought to be caused by expansion of disease-related TCR clonotypes. However, how biological agents affect the TCR repertoire status and whether their therapeutic outcomes are associated with certain features or dynamic patterns of the TCR repertoire are still elusive. We collected clinical samples from AS patients pre- and post-treatment with biologics. TCR repertoire sequencing was conducted to investigate associations of TCRα and TCRβ repertoire characteristics with disease activity and inflammatory indicators/cytokines. Our results showed that good responders were associated with an increase in the TCR repertoire diversity with higher proportions of contracted TCR clonotypes. Additionally, we further identified a positive correlation between TCR repertoire diversity and interleukin (IL)–23 levels in AS patients. A network analysis revealed that contracted AS-associated TCR clonotypes with the same complementary-determining region 3 (CDR3) motifs, which represented high probabilities of sharing TCR specificities to AS-related antigens, were dominant in good responders of AS after treatment with biologic therapies. Our findings suggested an important connection between TCR repertoire changes and therapeutic outcomes in biologic-treated AS patients. The status and dynamics of TCR repertoire profiles are useful for assessing the prognosis of biologic treatments in AS patients. [ABSTRACT FROM AUTHOR]

The tissue-specific drivers of neurosarcoidosis remain poorly defined. To identify cerebrospinal fluid (CSF) specific, antigen-driven T and B cell responses, we performed single-cell RNA sequencing of CSF and blood cells from neurosarcoid participants coupled to T and B cell receptor sequencing. In contrast to pulmonary sarcoidosis, which is driven by CD4 T cells, we found CD8 T cell clonal expansion enriched in the neurosarcoid CSF. These CSF-enriched CD8 T cells were composed of two subsets with differential expression of EBI2, CXCR3, and CXCR4. Lastly, our data suggest that IFNγ signaling may distinguish neurosarcoidosis from other neurological disorders. [Display omitted] • The CSF from neurosarcoidosis contains consistent clonal expansion of CD8 T cells, but not CD4 T cells. • CSF-enriched CD8 T cell clones express CD27, EBI2, and Granzyme K in both the CSF and the blood. • An interferon signature marks CSF CD8 T cells in neurosarcoidosis. • Elevated CSF levels of IFNγ distinguish active neurosarcoidosis from other CNS disorders. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinomas (ccRCCs) are highly immune infiltrated, but the effect of immune heterogeneity on clinical outcome in ccRCC has not been fully characterized. Here we perform paired single-cell RNA (scRNA) and T cell receptor (TCR) sequencing of 167,283 cells from multiple tumor regions, lymph node, normal kidney, and peripheral blood of two immune checkpoint blockade (ICB)-naïve and four ICB-treated patients to map the ccRCC immune landscape. We detect extensive heterogeneity within and between patients, with enrichment of CD8A + tissue-resident T cells in a patient responsive to ICB and tumor-associated macrophages (TAMs) in a resistant patient. A TCR trajectory framework suggests distinct T cell differentiation pathways between patients responding and resistant to ICB. Finally, scRNA-derived signatures of tissue-resident T cells and TAMs are associated with response to ICB and targeted therapies across multiple independent cohorts. Our study establishes a multimodal interrogation of the cellular programs underlying therapeutic efficacy in ccRCC. [Display omitted] • Single-cell RNA-seq reveals the architecture of the ccRCC immune microenvironment • Multiregional immune phenotypes integrated with bulk RNA-seq and tumor pathology • TCR usage varies by phenotype and defines T cell differentiation trajectories • Signatures of tissue-resident T cells and TAMs predict clinical outcome Krishna et al. dissect the immune microenvironment and TCR clonotype dynamics in multiregional clear cell renal cell carcinoma (ccRCC) samples at single-cell resolution. They show that CD8+ tissue-resident T cells and distinct tumor-associated macrophage (TAM) populations are associated with response and resistance to immune checkpoint blockade (ICB) in ccRCC. [ABSTRACT FROM AUTHOR]