Dataset Information

Intestinal CD8⁺ T cell responses are abundantly induced early in human development but show impaired cytotoxic effector capacities.

ABSTRACT: Gastrointestinal viral infections are a major global cause of disease and mortality in infants. Cytotoxic CD8⁺ T cells are critical to achieve viral control. However, studies investigating the development of CD8⁺ T cell immunity in human tissues early in life are lacking. Here, we investigated the maturation of the CD8⁺ T cell compartment in human fetal, infant and adult intestinal tissues. CD8⁺ T cells exhibiting a memory phenotype were already detected in fetal intestines and increased after birth. Infant intestines preferentially harbored effector CCR7^-CD45RA^-CD127^-KLRG1^+/- CD8⁺ T cells compared to tissue-resident memory CD69⁺CD103⁺CD8⁺ T cells detected in adults. Functional cytotoxic capacity, including cytokine and granzyme B production of infant intestinal effector CD8⁺ T cells was, however, markedly reduced compared to adult intestinal CD8⁺ T cells. This was in line with the high expression of the inhibitory molecule PD-1 by infant intestinal effector CD8⁺ T cells. Taken together, we demonstrate that intestinal CD8⁺ T cell responses are induced early in human development, however exhibit a reduced functionality. The impaired CD8⁺ T cell functionality early in life contributes to tolerance during foreign antigen exposure after birth, however functions as an immune correlate for the increased susceptibility to gastrointestinal viral infections in infancy.

SUBMITTER: Schreurs RRCE

PROVIDER: S-EPMC8075922 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Intestinal CD8+ T cell responses are abundantly induced early in human development but show impaired cytotoxic effector capacities.

Schreurs R R C E RRCE Sagebiel A F AF Steinert F L FL Highton A J AJ Klarenbeek P L PL Drewniak A A Bakx R R The S M L SML Ribeiro C M S CMS Perez D D Reinshagen K K Geijtenbeek T B H TBH van Goudoever J B JB Bunders M J MJ

Mucosal immunology 20210326 3

Gastrointestinal viral infections are a major global cause of disease and mortality in infants. Cytotoxic CD8+ T cells are critical to achieve viral control. However, studies investigating the development of CD8+ T cell immunity in human tissues early in life are lacking. Here, we investigated the maturation of the CD8+ T cell compartment in human fetal, infant and adult intestinal tissues. CD8+ T cells exhibiting a memory phenotype were already detect ...[more]

PMID: 33772147

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Project description:As humans age, their memory T cell compartment expands due to the lifelong exposure to antigens. This expansion is characterized by terminally differentiated CD8+ T cells (Temra), which possess NK cell-like phenotype and are associated with chronic inflammatory conditions. Temra cells are predominantly driven by the sporadic reactivation of cytomegalovirus (CMV), yet their epigenomic patterns and cellular heterogeneity remain understudied. To address this gap, we correlated their gene expression profiles with chromatin openness and conducted single-cell transcriptome analysis, comparing them to other CD8+ subsets and CMV-responses. We confirmed that Temra cells exhibit high expression of genes associated with cytotoxicity and lower expression of costimulatory and chemokine genes. The data revealed that CMV-responsive CD8+ T cells (Tcmv) were predominantly derived from a mixed population of Temra and memory cells (Tcm/em) and shared their transcriptomic profiles. Using ATAC-seq analysis, we identified 1449 differentially accessible chromatin regions between CD8+ Temra and Tcm/em cells, of which only 127 sites gained chromatin accessibility in Temra cells. We further identified 51 gene loci, including costimulatory CD27, CD28, and ICOS genes, whose chromatin accessibility correlated with their gene expression. The differential chromatin regions Tcm/em cells were enriched in motifs that bind multiple transcriptional activators, such as Jun/Fos, NFkappaB, and STAT, whereas the open regions in Temra cells mainly contained binding sites of T-box transcription factors. Our single-cell analysis of CD8+CCR7loCD45RAhi sorted Temra population showed several subsets of Temra and NKT-like cells and CMC1+ Temra populations in older individuals that were shifted towards decreased cytotoxicity. Among CD8+CCR7loCD45RAhi sorted cells, we found a decreased proportion of IL7R+ Tcm/em-like and MAIT cells in individuals with high levels of CMV antibodies (CMVhi). These results shed new light on the molecular and cellular heterogeneity of CD8+ Temra cells and their relationship to aging and CMV infection.

Dataset Information

Intestinal CD8⁺ T cell responses are abundantly induced early in human development but show impaired cytotoxic effector capacities.

Publications

Intestinal CD8<sup>+</sup> T cell responses are abundantly induced early in human development but show impaired cytotoxic effector capacities.

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