Limits...
Functional perturbation of classical natural killer and innate lymphoid cells in the oral mucosa during SIV infection.

Li H, Reeves RK - Front Immunol (2013)

Bottom Line: Also in contrast to what we have previously found in gut tissues of SIV-infected macaques, we found no reduction in NK cells during chronic SIV infection, but rather an expansion of ILCs in oral-draining lymph nodes and tonsils.These data suggest that the lentivirus-induced depletion of the NK cell/ILC compartment in the gut may be absent in the oral mucosa, but the inherent differences and SIV-induced alterations are likely to have significant impact on preventing oral opportunistic infections in lentiviral disease.Furthermore, these data extend our understanding of the oral innate immune system in general and could aid future studies evaluating the regulation of both normal oral flora and limiting transmission of oral mucosal pathogens.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, New England Primate Research Center, Harvard Medical School, One Pine Hill Drive Southborough, MA, USA.

ABSTRACT
Despite the fact that the majority of human pathogens are transmitted across mucosal surfaces, including the oral mucosae, oral immunity is poorly understood. Furthermore, because the normal flora of the oral cavity is vast and significantly diverse, host immunity must balance a complex system of tolerance and pathogen recognition. Due to the rapid recognition and response to pathogens, the innate immune system, including natural killer (NK) cells, likely plays a critical role in mediating this balance. Because logistical and ethical restraints limit access to significant quantities of human mucosal tissues, non-human primate models offer one of the best opportunities to study mucosal NK cells. In this study we have identified both classical NK cells, as well as innate lymphoid cells (ILCs) in tonsillar and buccal tissues and oral-draining lymph nodes. Identified by mutually exclusive expression of NKG2A and NKp44, NK cells, and ILCs in the oral mucosa are generally phenotypically and functionally analogous to their gut counterparts. NKG2A(+) NK cells were more cytotoxic while NKp44(+) ILCs produced copious amounts of IL-17 and TNF-α. However, in contrast to gut, oral NK cells and ILCs both produced large quantities of IFN-γ and the beta-chemokine, MIP-1β. Also in contrast to what we have previously found in gut tissues of SIV-infected macaques, we found no reduction in NK cells during chronic SIV infection, but rather an expansion of ILCs in oral-draining lymph nodes and tonsils. These data suggest that the lentivirus-induced depletion of the NK cell/ILC compartment in the gut may be absent in the oral mucosa, but the inherent differences and SIV-induced alterations are likely to have significant impact on preventing oral opportunistic infections in lentiviral disease. Furthermore, these data extend our understanding of the oral innate immune system in general and could aid future studies evaluating the regulation of both normal oral flora and limiting transmission of oral mucosal pathogens.

No MeSH data available.


Related in: MedlinePlus

Chronic SIV infection induces an expansion of NKp44+ ILC frequencies in the oral mucosa. Frequencies of NKG2A+ NK cells (A) and NKp44+ ILCs (B) among live CD45+CD3− mononuclear cells in oral tissues of naïve and SIV-infected macaques. Horizontal lines indicate medians of 4–8 animals per group. Mann–Whitney U-tests were used for naïve-vs.-SIV comparisons; *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3539714&req=5

Figure 4: Chronic SIV infection induces an expansion of NKp44+ ILC frequencies in the oral mucosa. Frequencies of NKG2A+ NK cells (A) and NKp44+ ILCs (B) among live CD45+CD3− mononuclear cells in oral tissues of naïve and SIV-infected macaques. Horizontal lines indicate medians of 4–8 animals per group. Mann–Whitney U-tests were used for naïve-vs.-SIV comparisons; *P < 0.05.

Mentions: We know that NKG2A+ NK cells and NKp44+ ILCs play critical immune defense and homeostatic roles in the mucosa, and we have recently shown that lentivirus infection has a significant negative impact on both cell types (Reeves et al., 2011). Therefore, we next enumerated and evaluated functionally NK cells and ILCs in oral mucosal tissues of SIV-infected and naïve macaques. Although both classical NK cells and ILCs trended toward increase in tonsils and OLN of SIV-infected compared to naïve macaques, only the expansion of ILCs was significant (Figure 4). This finding was in stark contrast to our previous observations for other mucosal sites, such as the colorectal mucosa, where ILCs are massively depleted and classical NK cells are reduced (Reeves et al., 2011). Furthermore, no association of either oral NK cell or oral ILC numbers was found with plasma viral load, nor was there any direct evidence of increased apoptosis (data not shown), two trends found in colorectal mucosa (Reeves et al., 2011). However, similar to what we have observed in other mucosal sites, NK cell and ILC function in oral tissues was significantly altered during SIV infection. ILCs had nearly a 3-fold increase in intracellular perforin expression in tonsils, as well as a modest, but significant, upregulation of perforin in OLN (Figure 5A). NK cells similarly upregulated intracellular perforin in tonsil and upon stimulation, both NK cells and ILCs from SIV-infected animals upregulated CD107a, a surrogate marker of degranulation and cytotoxicity (Figures 5A,B). CD107a upregulation was, however, only significant in ILCs where the increase was particularly robust (median frequency CD107a expression, naïve −4.5%, SIV-infected −25%). Furthermore, as we have previously found for colorectal tissues, SIV infection induced a loss of IL-17 production in lieu of upregulated TNF-α and IFN-γ production by ILCs. Interestingly, both cell populations produced similar levels of MIP-1β regardless of infection status. Using multiparametric analysis we found very little difference in the multi-function profiles of NKG2A+ NK cells (Figure 5C). However, NKp44+ did exhibit a significant increase (p = 0.01) in overlapping functions, most notably the increase in TNF-α+IFN-γ+MIP-1β+ cells with and without the SIV-induced upregulation of degranulation marker, CD107a.


Functional perturbation of classical natural killer and innate lymphoid cells in the oral mucosa during SIV infection.

Li H, Reeves RK - Front Immunol (2013)

Chronic SIV infection induces an expansion of NKp44+ ILC frequencies in the oral mucosa. Frequencies of NKG2A+ NK cells (A) and NKp44+ ILCs (B) among live CD45+CD3− mononuclear cells in oral tissues of naïve and SIV-infected macaques. Horizontal lines indicate medians of 4–8 animals per group. Mann–Whitney U-tests were used for naïve-vs.-SIV comparisons; *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539714&req=5

Figure 4: Chronic SIV infection induces an expansion of NKp44+ ILC frequencies in the oral mucosa. Frequencies of NKG2A+ NK cells (A) and NKp44+ ILCs (B) among live CD45+CD3− mononuclear cells in oral tissues of naïve and SIV-infected macaques. Horizontal lines indicate medians of 4–8 animals per group. Mann–Whitney U-tests were used for naïve-vs.-SIV comparisons; *P < 0.05.
Mentions: We know that NKG2A+ NK cells and NKp44+ ILCs play critical immune defense and homeostatic roles in the mucosa, and we have recently shown that lentivirus infection has a significant negative impact on both cell types (Reeves et al., 2011). Therefore, we next enumerated and evaluated functionally NK cells and ILCs in oral mucosal tissues of SIV-infected and naïve macaques. Although both classical NK cells and ILCs trended toward increase in tonsils and OLN of SIV-infected compared to naïve macaques, only the expansion of ILCs was significant (Figure 4). This finding was in stark contrast to our previous observations for other mucosal sites, such as the colorectal mucosa, where ILCs are massively depleted and classical NK cells are reduced (Reeves et al., 2011). Furthermore, no association of either oral NK cell or oral ILC numbers was found with plasma viral load, nor was there any direct evidence of increased apoptosis (data not shown), two trends found in colorectal mucosa (Reeves et al., 2011). However, similar to what we have observed in other mucosal sites, NK cell and ILC function in oral tissues was significantly altered during SIV infection. ILCs had nearly a 3-fold increase in intracellular perforin expression in tonsils, as well as a modest, but significant, upregulation of perforin in OLN (Figure 5A). NK cells similarly upregulated intracellular perforin in tonsil and upon stimulation, both NK cells and ILCs from SIV-infected animals upregulated CD107a, a surrogate marker of degranulation and cytotoxicity (Figures 5A,B). CD107a upregulation was, however, only significant in ILCs where the increase was particularly robust (median frequency CD107a expression, naïve −4.5%, SIV-infected −25%). Furthermore, as we have previously found for colorectal tissues, SIV infection induced a loss of IL-17 production in lieu of upregulated TNF-α and IFN-γ production by ILCs. Interestingly, both cell populations produced similar levels of MIP-1β regardless of infection status. Using multiparametric analysis we found very little difference in the multi-function profiles of NKG2A+ NK cells (Figure 5C). However, NKp44+ did exhibit a significant increase (p = 0.01) in overlapping functions, most notably the increase in TNF-α+IFN-γ+MIP-1β+ cells with and without the SIV-induced upregulation of degranulation marker, CD107a.

Bottom Line: Also in contrast to what we have previously found in gut tissues of SIV-infected macaques, we found no reduction in NK cells during chronic SIV infection, but rather an expansion of ILCs in oral-draining lymph nodes and tonsils.These data suggest that the lentivirus-induced depletion of the NK cell/ILC compartment in the gut may be absent in the oral mucosa, but the inherent differences and SIV-induced alterations are likely to have significant impact on preventing oral opportunistic infections in lentiviral disease.Furthermore, these data extend our understanding of the oral innate immune system in general and could aid future studies evaluating the regulation of both normal oral flora and limiting transmission of oral mucosal pathogens.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, New England Primate Research Center, Harvard Medical School, One Pine Hill Drive Southborough, MA, USA.

ABSTRACT
Despite the fact that the majority of human pathogens are transmitted across mucosal surfaces, including the oral mucosae, oral immunity is poorly understood. Furthermore, because the normal flora of the oral cavity is vast and significantly diverse, host immunity must balance a complex system of tolerance and pathogen recognition. Due to the rapid recognition and response to pathogens, the innate immune system, including natural killer (NK) cells, likely plays a critical role in mediating this balance. Because logistical and ethical restraints limit access to significant quantities of human mucosal tissues, non-human primate models offer one of the best opportunities to study mucosal NK cells. In this study we have identified both classical NK cells, as well as innate lymphoid cells (ILCs) in tonsillar and buccal tissues and oral-draining lymph nodes. Identified by mutually exclusive expression of NKG2A and NKp44, NK cells, and ILCs in the oral mucosa are generally phenotypically and functionally analogous to their gut counterparts. NKG2A(+) NK cells were more cytotoxic while NKp44(+) ILCs produced copious amounts of IL-17 and TNF-α. However, in contrast to gut, oral NK cells and ILCs both produced large quantities of IFN-γ and the beta-chemokine, MIP-1β. Also in contrast to what we have previously found in gut tissues of SIV-infected macaques, we found no reduction in NK cells during chronic SIV infection, but rather an expansion of ILCs in oral-draining lymph nodes and tonsils. These data suggest that the lentivirus-induced depletion of the NK cell/ILC compartment in the gut may be absent in the oral mucosa, but the inherent differences and SIV-induced alterations are likely to have significant impact on preventing oral opportunistic infections in lentiviral disease. Furthermore, these data extend our understanding of the oral innate immune system in general and could aid future studies evaluating the regulation of both normal oral flora and limiting transmission of oral mucosal pathogens.

No MeSH data available.


Related in: MedlinePlus