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NK cells in mucosal defense against infection.

Ivanova D, Krempels R, Ryfe J, Weitzman K, Stephenson D, Gigley JP - Biomed Res Int (2014)

Bottom Line: Mucosal NK cells play a pivotal role in early protection through their cytolytic function and IFNγ production against bacteria, fungi, viruses, and parasitic infections.The question of how they come to reside in their tissues and published data on their function against pathogens during mucosal infection are discussed.Dissecting major questions highlighted in this review will be important to the further understanding of NK cell homing and functional diversity and improve rational design of NK cell based therapies against mucosal infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, 6005 Agriculture C Building, University of Wyoming, Laramie, WY 82071, USA.

ABSTRACT
Conventional natural killer cells (NK cells) provide continual surveillance for cancer and rapid responses to infection. They develop in the bone marrow, emerge as either NK precursor cells, immature, or mature cells, and disperse throughout the body. In the periphery NK cells provide critical defense against pathogens and cancer and are noted to develop features of adaptive immune responses. In the tightly regulated and dynamic mucosal tissues, they set up residency via unknown mechanisms and from sources that are yet to be defined. Once resident, they appear to have the ability to functionally mature dependent on the mucosal tissue microenvironment. Mucosal NK cells play a pivotal role in early protection through their cytolytic function and IFNγ production against bacteria, fungi, viruses, and parasitic infections. This review presents what is known about NK cell development and phenotypes of mucosal tissue resident conventional NK cells. The question of how they come to reside in their tissues and published data on their function against pathogens during mucosal infection are discussed. Dissecting major questions highlighted in this review will be important to the further understanding of NK cell homing and functional diversity and improve rational design of NK cell based therapies against mucosal infection.

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Related in: MedlinePlus

Lung mucosa NK cells. NK cells found in the lung during the steady state exhibit a mature phenotype being CD27loCD11bhi in mice and CD56dim⁡ CD16+ in humans suggesting that after development in the bone marrow immature (iNK, pink) and or mature (mNK, green) NK cells found in the blood home to the lung and may not require a specific signal or cell-cell interaction in a secondary lymphoid organ to migrate. Lung microbiome could impact NK cell development and/or function. During infection by a pathogen (red circle), dendritic cells in the lamina propria of the lung are triggered via pattern recognition receptors (PRRs) to produce inflammatory cytokines including IL-12 and IL-23. This in combination with recognition of infected cells by activating receptors (Ly49 mouse, KIR human, NKp both) on NK cells results in activation of resident NK cell populations to produce IFNγ, IL-17, and be cytolytic (CTL).
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fig1: Lung mucosa NK cells. NK cells found in the lung during the steady state exhibit a mature phenotype being CD27loCD11bhi in mice and CD56dim⁡ CD16+ in humans suggesting that after development in the bone marrow immature (iNK, pink) and or mature (mNK, green) NK cells found in the blood home to the lung and may not require a specific signal or cell-cell interaction in a secondary lymphoid organ to migrate. Lung microbiome could impact NK cell development and/or function. During infection by a pathogen (red circle), dendritic cells in the lamina propria of the lung are triggered via pattern recognition receptors (PRRs) to produce inflammatory cytokines including IL-12 and IL-23. This in combination with recognition of infected cells by activating receptors (Ly49 mouse, KIR human, NKp both) on NK cells results in activation of resident NK cell populations to produce IFNγ, IL-17, and be cytolytic (CTL).

Mentions: 10% of total lung resident lymphocytes are NK cells. This is a higher NK cell number than other nonlymphoid organs highlighting their importance in this tissue [24]. They are primarily found along with other lymphocytes in the lung epithelium and vascular tissues [24, 25]. In humans, lung resident NK cells are CD56dim⁡ CD16+ and mostly NKp46+ similar to NK cells in the blood suggesting a mature phenotype capable of being cytotoxic and producing cytokines [26]. In mice the more mature NK cell phenotype is found in the lung epithelium, which is CD27lo  CD11bhi, very similar in function to the human subset. In the naïve state, these two phenotypes of NK cells in both human and mouse compose 80–90% of all NK cells present in the lung tissue [13, 25]. The maturation status of most lung NK cells resembles those from blood. However a recent study identified a population of NK cells in the lung capable of being further differentiated [27]. This study demonstrated that, unlike bone marrow precursors, the lung precursor cells when cultured in vitro expressed more Ly49 receptors. These results suggest that both mature and immature NK cells are present in the lung and that the murine lung microenvironment could condition NK cells separately from the bone marrow. In humans, other than classical NK cell marker phenotype (CD56 and CD16) approximately 30% of lung resident NK cells express KIRs including KIR2DL2, KIR2DL3, KIR3DL1 and KIR2DS2. Nearly 80% of the CD56bright population expressed CD94 similar to the phenotypes found in peripheral blood [26, 28]. Murine and human lung microenvironments may differ in their ability to modify resident NK cells. In humans support for tissue specific microenvironment conditioning of NK cells comes from studies of pulmonary sarcoidosis and non-small-cell lung cancer [26, 28]. NK cells express less KIR in bronchiolar lavage fluid (BALF) in these situations than in the naïve state. Interestingly, peripheral blood NK cells also had lower KIR expression. Whether or not the change observed in BALF was from migrating cells is not known. The observations in BALF support a role for tissue specific microenvironment conditioning of NK cells. However, the more mature phenotype of resident NK cells in the lung is suggestive of a blood origin (Figure 1). Currently, much is still not known about the mechanisms behind these changes and whether in the healthy state tissue resident human NK cell phenotypes can be modified by the lung.


NK cells in mucosal defense against infection.

Ivanova D, Krempels R, Ryfe J, Weitzman K, Stephenson D, Gigley JP - Biomed Res Int (2014)

Lung mucosa NK cells. NK cells found in the lung during the steady state exhibit a mature phenotype being CD27loCD11bhi in mice and CD56dim⁡ CD16+ in humans suggesting that after development in the bone marrow immature (iNK, pink) and or mature (mNK, green) NK cells found in the blood home to the lung and may not require a specific signal or cell-cell interaction in a secondary lymphoid organ to migrate. Lung microbiome could impact NK cell development and/or function. During infection by a pathogen (red circle), dendritic cells in the lamina propria of the lung are triggered via pattern recognition receptors (PRRs) to produce inflammatory cytokines including IL-12 and IL-23. This in combination with recognition of infected cells by activating receptors (Ly49 mouse, KIR human, NKp both) on NK cells results in activation of resident NK cell populations to produce IFNγ, IL-17, and be cytolytic (CTL).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150440&req=5

fig1: Lung mucosa NK cells. NK cells found in the lung during the steady state exhibit a mature phenotype being CD27loCD11bhi in mice and CD56dim⁡ CD16+ in humans suggesting that after development in the bone marrow immature (iNK, pink) and or mature (mNK, green) NK cells found in the blood home to the lung and may not require a specific signal or cell-cell interaction in a secondary lymphoid organ to migrate. Lung microbiome could impact NK cell development and/or function. During infection by a pathogen (red circle), dendritic cells in the lamina propria of the lung are triggered via pattern recognition receptors (PRRs) to produce inflammatory cytokines including IL-12 and IL-23. This in combination with recognition of infected cells by activating receptors (Ly49 mouse, KIR human, NKp both) on NK cells results in activation of resident NK cell populations to produce IFNγ, IL-17, and be cytolytic (CTL).
Mentions: 10% of total lung resident lymphocytes are NK cells. This is a higher NK cell number than other nonlymphoid organs highlighting their importance in this tissue [24]. They are primarily found along with other lymphocytes in the lung epithelium and vascular tissues [24, 25]. In humans, lung resident NK cells are CD56dim⁡ CD16+ and mostly NKp46+ similar to NK cells in the blood suggesting a mature phenotype capable of being cytotoxic and producing cytokines [26]. In mice the more mature NK cell phenotype is found in the lung epithelium, which is CD27lo  CD11bhi, very similar in function to the human subset. In the naïve state, these two phenotypes of NK cells in both human and mouse compose 80–90% of all NK cells present in the lung tissue [13, 25]. The maturation status of most lung NK cells resembles those from blood. However a recent study identified a population of NK cells in the lung capable of being further differentiated [27]. This study demonstrated that, unlike bone marrow precursors, the lung precursor cells when cultured in vitro expressed more Ly49 receptors. These results suggest that both mature and immature NK cells are present in the lung and that the murine lung microenvironment could condition NK cells separately from the bone marrow. In humans, other than classical NK cell marker phenotype (CD56 and CD16) approximately 30% of lung resident NK cells express KIRs including KIR2DL2, KIR2DL3, KIR3DL1 and KIR2DS2. Nearly 80% of the CD56bright population expressed CD94 similar to the phenotypes found in peripheral blood [26, 28]. Murine and human lung microenvironments may differ in their ability to modify resident NK cells. In humans support for tissue specific microenvironment conditioning of NK cells comes from studies of pulmonary sarcoidosis and non-small-cell lung cancer [26, 28]. NK cells express less KIR in bronchiolar lavage fluid (BALF) in these situations than in the naïve state. Interestingly, peripheral blood NK cells also had lower KIR expression. Whether or not the change observed in BALF was from migrating cells is not known. The observations in BALF support a role for tissue specific microenvironment conditioning of NK cells. However, the more mature phenotype of resident NK cells in the lung is suggestive of a blood origin (Figure 1). Currently, much is still not known about the mechanisms behind these changes and whether in the healthy state tissue resident human NK cell phenotypes can be modified by the lung.

Bottom Line: Mucosal NK cells play a pivotal role in early protection through their cytolytic function and IFNγ production against bacteria, fungi, viruses, and parasitic infections.The question of how they come to reside in their tissues and published data on their function against pathogens during mucosal infection are discussed.Dissecting major questions highlighted in this review will be important to the further understanding of NK cell homing and functional diversity and improve rational design of NK cell based therapies against mucosal infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, 6005 Agriculture C Building, University of Wyoming, Laramie, WY 82071, USA.

ABSTRACT
Conventional natural killer cells (NK cells) provide continual surveillance for cancer and rapid responses to infection. They develop in the bone marrow, emerge as either NK precursor cells, immature, or mature cells, and disperse throughout the body. In the periphery NK cells provide critical defense against pathogens and cancer and are noted to develop features of adaptive immune responses. In the tightly regulated and dynamic mucosal tissues, they set up residency via unknown mechanisms and from sources that are yet to be defined. Once resident, they appear to have the ability to functionally mature dependent on the mucosal tissue microenvironment. Mucosal NK cells play a pivotal role in early protection through their cytolytic function and IFNγ production against bacteria, fungi, viruses, and parasitic infections. This review presents what is known about NK cell development and phenotypes of mucosal tissue resident conventional NK cells. The question of how they come to reside in their tissues and published data on their function against pathogens during mucosal infection are discussed. Dissecting major questions highlighted in this review will be important to the further understanding of NK cell homing and functional diversity and improve rational design of NK cell based therapies against mucosal infection.

Show MeSH
Related in: MedlinePlus