Heterogeneity and clonal relationships of adaptive immune cells in ulcerative colitis revealed by single-cell analyses

Abstract

Inflammatory bowel disease (IBD) encompasses a spectrum of gastrointestinal disorders driven by dysregulated immune responses against gut microbiota. We integrated single-cell RNA and antigen receptor sequencing to elucidate key components, cellular states, and clonal relationships of the peripheral and gastrointestinal mucosal immune systems in health and ulcerative colitis (UC). UC was associated with an increase in IgG1+ plasma cells in colonic tissue, increased colonic regulatory T cells characterized by elevated expression of the transcription factor ZEB2, and an enrichment of a γδ T cell subset in the peripheral blood. Moreover, we observed heterogeneity in CD8+ tissue-resident memory T (TRM) cells in colonic tissue, with four transcriptionally distinct states of differentiation observed across health and disease. In the setting of UC, there was a marked shift of clonally related CD8+ TRM cells toward an inflammatory state, mediated, in part, by increased expression of the T-box transcription factor Eomesodermin. Together, these results provide a detailed atlas of transcriptional changes occurring in adaptive immune cells in the context of UC and suggest a role for CD8+ TRM cells in IBD.

Balancing Inflammation and Central Nervous System Homeostasis: T Cell Receptor Signaling in Antiviral Brain TRM Formation and Function

“…MuPyV-specific CD8 bT RM heterogeneously express many molecules associated with T EX subsets ( 36 , 87 ). Single-cell analysis of adaptive immune cells in ulcerative colitis patients suggests that transcriptional heterogeneity also exists in the T RM compartment and its demarcation into distinct differentiation stages ( 99 ). Similarly, lung CD8 T RM generated to influenza infection exhibit both exhausted and memory characteristics by phenotype, transcriptome, and function ( 80 ).…”

IL-21 in Homeostasis of Resident Memory and Exhausted CD8 T Cells during Persistent Infection

“…A recent study of T cells in human brains also found a 40/60% split of CD103 + /CD103 − CD8 T cells; there, CD103 expression correlated with upregulation of homing markers, but without a difference in localization [67]. Interestingly, in both mice and humans, there appears to be an inverse relationship between PD-1 and CD103 expression by CD8 T RM [43,68]. Thus, CD103 expression is an imperfect T RM marker and may not be involved in CNS localization; moreover, whether PD-1 regulates CD103 expression or possibly fosters survival of CD103 − CD8 T cells remains to be determined.…”

“…In addition, Eomes is associated with promoting self-renewal of memory cells [96] and is upregulated by CD8 T cells during chronic infection [97]. A recent study has shown increased expression of Eomes by an inflammatory subset of CD8 T RM isolated from rectal mucosa of patients with ulcerative colitis [68].…”

Total Recall: Intestinal TRM Cells in Health and Disease

“…KLRG1 + CD8 + T RM cells were specifically elevated under inflammatory conditions and showed increased proliferative and cytotoxic potential ( 61 ). Furthermore, a recent study employing single-cell RNA-sequencing identified changes in the transcriptional profile of CD8 + T RM cell subsets in UC including a pro-inflammatory phenotype and increased expression of Eomesodermin ( 62 ). Similarly, Corridoni and colleagues reported that CD8 + T RM cells in UC express more GZMK and IL26, suggesting that altered CD8 + T RM cells are implicated in UC pathogenesis ( 63 ).…”