Molecular determinants and heterogeneity of tissue-resident memory CD8⁺T lymphocytes revealed by single-cell RNA sequencing

Abstract

One sentence summary: Here, we applied single-cell RNA-sequencing to elucidate the gene expression patterns of individual CD8 + T cells differentiating throughout the course of infection in the spleen and small intestinal epithelium, which revealed previously unidentified molecular determinants of tissue-resident T cell differentiation as well as functional heterogeneity within the tissue-resident CD8 + T cell population. Abstract: During an immune response to microbial infection, CD8 + T cells give rise to distinct classes of cellular progeny that coordinately mediate clearance of the pathogen and provide long-lasting protection against reinfection, including a subset of noncirculating tissue-resident memory (TRM) cells that mediate potent protection within nonlymphoid tissues. Here, we utilized single-cell RNA-sequencing to examine the gene expression patterns of individual CD8 + T cells in the spleen and small intestine intraepithelial lymphocyte (siIEL) compartment throughout the course of their differentiation in response to viral infection. These analyses revealed previously unknown transcriptional heterogeneity within the siIEL CD8 + T cell population at several states of differentiation, representing functionally distinct TRM cell subsets as well as a subset of TRM cell precursors within the tissue early in infection. Taken together, these findings may inform strategies to optimize CD8 + T cell responses to protect against microbial infection and cancer.

Single-cell transcriptome profiling of an adult human cell atlas of 15 major organs

“…Moreover, trajectory analysis with TNF_T RM and STMN_T CM clusters revealed that TNF_T RM cells from two branches in an early state gradually progressed towards STMN1_T CM cells in a terminal state (Additional file 1: Figure S28A). T RM cells at the beginning of the trajectory expressed high levels of T RM markers, such as RUNX3, NR4A1, chemokines (CCL5) [59], and other T RM associated genes, including ID2 [60]. By contrast, T CM cells at the end of the trajectory were marked with expression of well-known T CM molecules, such as SELL and CCR7 (Additional file 1: Figure S28B).…”

Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection

“…As such, KLRG1 lo CD127 hi cells are referred to as memory precursor T cells (MP cells) and KLRG1 hi CD127 lo cells as terminal effector T cells (TE cells). MP cells display enhanced multipotency compared with TE cells and more efficiently give rise to central memory T cells (T CM cells), effector memory T cells (T EM cells), and tissue-resident memory T cells (T RM cells; Kaech et al, 2003 ; Mackay et al, 2013 ; Milner and Goldrath, 2018 ); however, select TE cells are able to persist for several months after infection, forming a terminally differentiated T EM cell population (t-T EM cells) or long-lived effector population ( Kurd et al, 2020 ; Milner et al, 2020a ; Milner et al, 2020b ; Olson et al, 2013 ). Canonical transcription factors known to regulate antiviral T cell differentiation include Id3 ( Ji et al, 2011 ; Yang et al, 2011 ), TCF1 ( Zhou et al, 2010 ), Bcl6 ( Ichii et al, 2002 ; Liu et al, 2019 ), STAT3 ( Cui et al, 2011 ), and Foxo1 ( Kim et al, 2013 ; Hess Michelini et al, 2013 ; Utzschneider et al, 2018 ) as critical regulators of MP/T CM cells , and Id2 ( Cannarile et al, 2006 ; Knell et al, 2013 ; Masson et al, 2013 ), Zeb2 ( Dominguez et al, 2015 ; Omilusik et al, 2015 ; Omilusik et al, 2018 ), Blimp1 ( Kallies et al, 2009 ; Rutishauser et al, 2009 ), STAT4 ( Mollo et al, 2014 ), and T-bet ( Joshi et al, 2007 ) are required for more terminally differentiated populations.…”

Immune cell residency in the nasal mucosa and COVID-19 severity across the age range

“…This transcriptional profile is very similar to that of resident-memory T lymphocytes (T rm ) (Schenkel and Masopust, 2014). T rm cells are known to occupy other tissues including the lungs in humans; they are important for local immune response there and can serve as a functional link between the innate and adaptative immune system (Bedford et al, 2020; Kurd et al, 2020; Steinbach et al, 2018; Sun et al, 2019). While T rm occupancy in the NM has yet to be described in humans, T rm are known to occupy the NM in mice and help to prevent pulmonary dissemination of influenza virus (Pizzolla et al, 2017) This characterization of NM T cells demonstrates the potential insights gleaned by profiling NM samples across the lifespan.…”