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CD8? T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung.

ABSTRACT: The human lung T cell compartment contains many CD8? T cells specific for respiratory viruses, suggesting that the lung is protected from recurring respiratory infections by a resident T cell pool. The entry site for respiratory viruses is the epithelium, in which a subset of lung CD8? T cells expressing CD103 (?E integrin) resides. Here, we determined the specificity and function of CD103?CD8? T cells in protecting human lung against viral infection. Mononuclear cells were isolated from human blood and lung resection samples. Variable numbers of CD103?CD8? T cells were retrieved from the lung tissue. Interestingly, expression of CD103 was seen only in lung CD8? T cells specific for influenza but not in those specific for EBV or CMV. CD103? and influenza-reactive cells preferentially expressed NKG2A, an inhibitor of CD8? T cell cytotoxic function. In contrast to CD103?CD8? T cells, most CD103?CD8? cells did not contain perforin or granzyme B. However, they could quickly upregulate these cytotoxic mediators when exposed to a type I IFN milieu or via contact with their specific antigen. This mechanism may provide a rapid and efficient response to influenza infection, without inducing cytotoxic damage to the delicate epithelial barrier.

SUBMITTER: Piet B

PROVIDER: S-EPMC3104744 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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CD8⁺ T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung.

Piet Berber B de Bree Godelieve J GJ Smids-Dierdorp Barbara S BS van der Loos Chris M CM Remmerswaal Ester B M EB von der Thüsen Jan H JH van Haarst Jan M W JM Eerenberg Jan P JP ten Brinke Anja A van der Bij Wim W Timens Wim W van Lier René A W RA Jonkers René E RE

The Journal of clinical investigation 20110502 6

The human lung T cell compartment contains many CD8⁺ T cells specific for respiratory viruses, suggesting that the lung is protected from recurring respiratory infections by a resident T cell pool. The entry site for respiratory viruses is the epithelium, in which a subset of lung CD8⁺ T cells expressing CD103 (αE integrin) resides. Here, we determined the specificity and function of CD103⁺CD8⁺ T cells in protecting human lung against viral infection. Mononuclear cells were isolated from human b ...[more]

PMID: 21537083

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Project description:Background & aimsIntraepithelial T lymphocyte cells (IEL) are the first immune cells to respond to pathogens; they help maintain the integrity of the epithelial barrier. We studied the function of the mouse glycoprotein Signaling Lymphocyte Activation Molecule Family receptor (SLAMF) 4 (encoded by Slamf4) on the surface of CD8αβ αβ T-cell receptor (TCR)(+) IELs, and the roles of these cells in homeostasis of the small intestine in mice.MethodsSLAMF4(-) CD8(+) αβTCR(+) cells isolated from spleens of OT-I Rag1(-/-) mice were induced to express gut-homing receptors and transferred to C57BL/6J mice; levels of SLAMF4(+) cells were measured in small intestine tissues. After administration of anti-CD3 or antigen, with or without anti-SLAM4, to C57BL/6J and Slamf4(-/-) mice, CD8αβ αβTCR(+) IELs were collected; cytokine production and cytotoxicity were measured. Depletion of CX3CR1(+) phagocytes was assessed in mice by live-cell confocal imaging or by cytofluorometry; small intestine tissues were analyzed by histology and inflammation was quantified.ResultsSplenic CD8(+) αβTCR(+) cells began to express SLAMF4 only after migrating to the small intestine. Injection of C57BL/6J mice with anti-SLAMF4 and anti-CD3 increased levels of interleukin 10 and interferon gamma secretion by IEL, compared with injection of anti-CD3 only. Similarly, the number of granzyme B(+) cytotoxic CD8(+) αβTCR(+) IELs increased in Slamf4(-/-) mice after injection of anti-CD3 and anti-SLAMF4, administration of antigen, or injection of anti-CD3. Surprisingly, in vivo activation of CD8αβ(+) IELs with anti-CD3 or antigen caused transient depletion of CX3CR1(+) phagocytes, which was prolonged by co-injection with anti-SLAMF4 or in Slamf4(-/-) mice. Anti-CD3 aggravated inflammation in the small intestines of Slamf4(-/-) mice and Eat2a(-/-)Eat2b(-/-) mice, indicated by flattened villi and crypt hyperplasia.ConclusionsIn mice, the intestinal environment induces SLAMF4 expression and localization to the surface of CD8(+) αβTCR(+) IELs. Signaling via SLAMF4 controls expansion of cytotoxic CD8αβ(+) IELs, which regulate the reversible depletion of lamina propria phagocytes and inflammation in the small intestine.

Dataset Information

CD8? T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung.

Publications

CD8⁺ T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung.

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