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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

Gut mucosal and female reproductive tract NK cells. NK cells found in the gut mucosa and FRT during the naive state exhibit an immature phenotype being CD27med-hiCD11bhi in mice and CD56brightCD16− in humans and resemble those NK cells found as residents in secondary lymphoid organs such as mesenteric lymph node (MLN) for the gut (top) and Iliac lymph node (ILN) for the FRT (bottom). This may suggest that gut and FRT resident NK cells are derived from NK precursors (NKP, pink), which migrate from bone marrow to lymph nodes (LN), where they differentiate into immature NK cells (iNK, blue cell in MLN, orange-red transition cell ILN). Dendritic cells (DC) draining from the lamina propria of the gut (CD103+) or DC from the FRT to the LN interact with immature NK cells and imprint the tissue address (α4β7/CCR9 for gut mucosa) that permits iNK cell homing to the correct tissues. In gut, NK cells can be IELs (orange cells) or in the LP (green cell) and respond to infectious pathogen (red circles) activated DCs and cytokine milieu in the tissue microenvironment becomes activated to produce IFNγ, IL-17, and/or CTL activity. In FRT, uterine NK cells (uNK, orange cell) have to balance help with fetal implantation via trophoblast recruitment, vascularization, and tolerance with ability to respond to pathogens. If stimulation of NK cells in response to a pathogen is high enough, IFNγ is expressed and may result in loss of pregnancy. Vaginal NK cells (iNK, brown) play an important role in containing invading pathogens via IFNγ production.
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fig2: Gut mucosal and female reproductive tract NK cells. NK cells found in the gut mucosa and FRT during the naive state exhibit an immature phenotype being CD27med-hiCD11bhi in mice and CD56brightCD16− in humans and resemble those NK cells found as residents in secondary lymphoid organs such as mesenteric lymph node (MLN) for the gut (top) and Iliac lymph node (ILN) for the FRT (bottom). This may suggest that gut and FRT resident NK cells are derived from NK precursors (NKP, pink), which migrate from bone marrow to lymph nodes (LN), where they differentiate into immature NK cells (iNK, blue cell in MLN, orange-red transition cell ILN). Dendritic cells (DC) draining from the lamina propria of the gut (CD103+) or DC from the FRT to the LN interact with immature NK cells and imprint the tissue address (α4β7/CCR9 for gut mucosa) that permits iNK cell homing to the correct tissues. In gut, NK cells can be IELs (orange cells) or in the LP (green cell) and respond to infectious pathogen (red circles) activated DCs and cytokine milieu in the tissue microenvironment becomes activated to produce IFNγ, IL-17, and/or CTL activity. In FRT, uterine NK cells (uNK, orange cell) have to balance help with fetal implantation via trophoblast recruitment, vascularization, and tolerance with ability to respond to pathogens. If stimulation of NK cells in response to a pathogen is high enough, IFNγ is expressed and may result in loss of pregnancy. Vaginal NK cells (iNK, brown) play an important role in containing invading pathogens via IFNγ production.

Mentions: Of the three innate lymphoid cell populations found in the gut, conventional NK cells of the gut are classified to belong to the ILC1 subset [1]. NK cells are present in all gut tissues (small intestine, large intestine, and colon) as cells of the IEL and LP compartments. They can also be found in smaller numbers in Peyer's patches (PP) and MLNs. Unlike the lung, gut mucosal NK cells in humans are predominantly CD56bright with few that express CD16 indicating that they may be similar to immature NK cells found in secondary lymphoid structures [29–31]. NK cells in the murine intestinal mucosa also appear immature. IEL and LP NK cells of naïve mice are CD27hiCD11bmed and CD27loCD11blo, respectively [32–34]. Further support for an immature phenotype for both murine and human gut NK cells is evident from functionality. Resident human CD56bright and mouse CD27hi NK cells produce large amounts of the proinflammatory cytokine IFNγ and exhibit low cytolytic activity when tested in vitro [19, 31]. After infection, significant changes occur in NK cell frequencies in the small intestine and lamina propria. Whether peripheral NK cell infiltration occurs or whether there are phenotypic changes in resident NK cell populations has not been investigated. Infiltration of peripheral blood NK cells probably occurs albeit to a lesser extent and the NK cell dependent response may rely more on an NK cell interaction with activated gut mucosal DCs in the MLN and/or expansion of activated LP NK cells at the site of infection (Figure 2). However, given the diversity of gut mucosal ILC populations with wide ranging function, determining the level of infiltration of new cells may be very difficult.


NK cells in mucosal defense against infection.

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

Gut mucosal and female reproductive tract NK cells. NK cells found in the gut mucosa and FRT during the naive state exhibit an immature phenotype being CD27med-hiCD11bhi in mice and CD56brightCD16− in humans and resemble those NK cells found as residents in secondary lymphoid organs such as mesenteric lymph node (MLN) for the gut (top) and Iliac lymph node (ILN) for the FRT (bottom). This may suggest that gut and FRT resident NK cells are derived from NK precursors (NKP, pink), which migrate from bone marrow to lymph nodes (LN), where they differentiate into immature NK cells (iNK, blue cell in MLN, orange-red transition cell ILN). Dendritic cells (DC) draining from the lamina propria of the gut (CD103+) or DC from the FRT to the LN interact with immature NK cells and imprint the tissue address (α4β7/CCR9 for gut mucosa) that permits iNK cell homing to the correct tissues. In gut, NK cells can be IELs (orange cells) or in the LP (green cell) and respond to infectious pathogen (red circles) activated DCs and cytokine milieu in the tissue microenvironment becomes activated to produce IFNγ, IL-17, and/or CTL activity. In FRT, uterine NK cells (uNK, orange cell) have to balance help with fetal implantation via trophoblast recruitment, vascularization, and tolerance with ability to respond to pathogens. If stimulation of NK cells in response to a pathogen is high enough, IFNγ is expressed and may result in loss of pregnancy. Vaginal NK cells (iNK, brown) play an important role in containing invading pathogens via IFNγ production.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Gut mucosal and female reproductive tract NK cells. NK cells found in the gut mucosa and FRT during the naive state exhibit an immature phenotype being CD27med-hiCD11bhi in mice and CD56brightCD16− in humans and resemble those NK cells found as residents in secondary lymphoid organs such as mesenteric lymph node (MLN) for the gut (top) and Iliac lymph node (ILN) for the FRT (bottom). This may suggest that gut and FRT resident NK cells are derived from NK precursors (NKP, pink), which migrate from bone marrow to lymph nodes (LN), where they differentiate into immature NK cells (iNK, blue cell in MLN, orange-red transition cell ILN). Dendritic cells (DC) draining from the lamina propria of the gut (CD103+) or DC from the FRT to the LN interact with immature NK cells and imprint the tissue address (α4β7/CCR9 for gut mucosa) that permits iNK cell homing to the correct tissues. In gut, NK cells can be IELs (orange cells) or in the LP (green cell) and respond to infectious pathogen (red circles) activated DCs and cytokine milieu in the tissue microenvironment becomes activated to produce IFNγ, IL-17, and/or CTL activity. In FRT, uterine NK cells (uNK, orange cell) have to balance help with fetal implantation via trophoblast recruitment, vascularization, and tolerance with ability to respond to pathogens. If stimulation of NK cells in response to a pathogen is high enough, IFNγ is expressed and may result in loss of pregnancy. Vaginal NK cells (iNK, brown) play an important role in containing invading pathogens via IFNγ production.
Mentions: Of the three innate lymphoid cell populations found in the gut, conventional NK cells of the gut are classified to belong to the ILC1 subset [1]. NK cells are present in all gut tissues (small intestine, large intestine, and colon) as cells of the IEL and LP compartments. They can also be found in smaller numbers in Peyer's patches (PP) and MLNs. Unlike the lung, gut mucosal NK cells in humans are predominantly CD56bright with few that express CD16 indicating that they may be similar to immature NK cells found in secondary lymphoid structures [29–31]. NK cells in the murine intestinal mucosa also appear immature. IEL and LP NK cells of naïve mice are CD27hiCD11bmed and CD27loCD11blo, respectively [32–34]. Further support for an immature phenotype for both murine and human gut NK cells is evident from functionality. Resident human CD56bright and mouse CD27hi NK cells produce large amounts of the proinflammatory cytokine IFNγ and exhibit low cytolytic activity when tested in vitro [19, 31]. After infection, significant changes occur in NK cell frequencies in the small intestine and lamina propria. Whether peripheral NK cell infiltration occurs or whether there are phenotypic changes in resident NK cell populations has not been investigated. Infiltration of peripheral blood NK cells probably occurs albeit to a lesser extent and the NK cell dependent response may rely more on an NK cell interaction with activated gut mucosal DCs in the MLN and/or expansion of activated LP NK cells at the site of infection (Figure 2). However, given the diversity of gut mucosal ILC populations with wide ranging function, determining the level of infiltration of new cells may be very difficult.

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