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. 2010 Jun 3;115(22):4439-46.
doi: 10.1182/blood-2010-01-265595. Epub 2010 Mar 25.

CD16- natural killer cells: enrichment in mucosal and secondary lymphoid tissues and altered function during chronic SIV infection

R Keith Reeves  1 , Jacqueline Gillis, Fay E Wong, Yi Yu, Michelle Connole, R Paul Johnson
Affiliations

CD16- natural killer cells: enrichment in mucosal and secondary lymphoid tissues and altered function during chronic SIV infection

R Keith Reeves et al. Blood. .

Abstract

Natural killer (NK) cells contribute to control of HIV/SIV infection. We defined macaque NK-cell subsets based on expression of CD56 and CD16 and found their distribution to be highly disparate VSports手机版. CD16(+) NK cells predominated in peripheral blood, whereas most mucosal NK cells were CD56(+), and lymph nodes contained both CD56(+) and CD16(-)CD56(-) (double-negative [DN]) subsets. Functional profiles were also distinct among subsets--CD16(+) NK cells expressed high levels of cytolytic molecules, and CD56(+) NK cells were predominantly cytokine-secreting cells, whereas DN NK possessed both functions. In macaques chronically infected with SIV, circulating CD16(+) and DN NK cells were expanded in number and, although markers of cytoxicity increased, cytokine secretion decreased. Notably, CD56(+) NK cells in SIV-infected animals up-regulated perforin, granzyme B, and CD107a. In contrast, the lymph node-homing molecules CD62 ligand (CD62L) and C-C chemokine receptor type 7 (CCR7), which are expressed primarily on CD56(+) and DN NK cells, were significantly down-regulated on NK cells from infected animals. These data demonstrate that SIV infection drives a shift in NK-cell function characterized by decreased cytokine production, expanded cytotoxicity, and trafficking away from secondary lymphoid organs, suggesting that the NK-cell repertoire is not only heterogeneous but also plastic. .

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"V体育安卓版" Figures

Figure 1
Figure 1
Phenotypic characterization of NK-cell subsets in peripheral blood of rhesus macaques. (A) Representative flow cytometric plots defining NK cells in PBMCs. Macaque NK cells were identified using a broad side- versus forward-scatter gate and phenotypically defined as CD3−CD8α+NKG2A+. Subsets were further delineated by expression of CD56 and/or CD16. (B) Representative histogram overlays depict expression of NKp46 and NKp30 on each of the 3 primary NK subsets. Gray closed histograms are from isotype-matched controls. CD56+ indicates CD56+CD16−; CD16+, CD56−CD16+; and DN, CD56−CD16−. Examples are representative of 15 to 27 naive animals.
Figure 2
Figure 2
Distribution of macaque NK-cell subsets in blood and tissues. (A) Representative flow cytometric plots showing distribution of NK subsets based on CD56 and CD16 expression in PBMCs and lymph node (LN), vaginal, and rectal biopsies (Bx) of uninfected rhesus macaques. (B) Frequencies of each of the NK-cell subsets are shown as a fraction of the total NK-cell population as defined in Figure 1. Horizontal bars represent medians of 9-15 animals.
Figure 3
Figure 3
Enumeration of absolute numbers of circulating NK-cell subsets in naive and SIV-infected macaques. Absolute numbers of total circulating NK cells were quantified in whole blood as previously described. NK subset counts were calculated as fractions of the total absolute counts using frequencies determined by polychromatic flow cytometry (Figure 1). (A) Counts from naive animals are compared with those from chronically infected animals, and only significant P values are shown. Horizontal bars indicate medians. Mann-Whitney test; *P < .05; **P < .01. (B) Absolute counts of peripheral blood DN NK cells correlated with plasma viral loads; Spearman correlation. P < .05 is considered significant.
Figure 4
Figure 4
Comparison of homing markers and chemokine receptors on NK-cell subsets in naive and SIV-infected macaques. Percentages of positive cells above background (CCR5, CCR6, CCR7, CD62L) and mean fluorescence intensities (CXCR3, CXCR4) were compared between naive and SIV-infected macaques for peripheral blood CD56+, CD16+, and DN NK subsets as shown in Figure 1. Horizontal bars indicate medians. Only significant P values are shown for naive versus SIV-infected comparisons. Mann-Whitney test; *P < .05; **P < .01; ***P < .001.
Figure 5
Figure 5
Increased expression of cytotoxic and activation markers on macaque NK-cell subsets from SIV-infected animals. (A) Representative polychromatic flow cytometric overlay depicting coordinate but variable expression of intracellular granzyme B and perforin by all peripheral blood NK subsets. (B) Mean fluorescence intensities of granzyme B (top panel) and perforin (bottom panel) and (C) percentages of positive cells above background of cell-surface CD69 are shown for each of the NK subsets in naive and SIV-infected animals. Only significant P values are shown for naive versus SIV-infected comparisons. Mann-Whitney test; *P < .05; **P < .01; ***P < .001.
Figure 6
Figure 6
Functionality of NK-cell subsets in naive and SIV-infected macaques. Percentages of peripheral blood NK-cell subsets positive for intracellular IFN-γ, TNF-α, MIP-1β, and CD107a in response to 721.221 cells. Horizontal bars indicate medians. Only significant P values are shown for naive versus SIV-infected comparisons. Mann-Whitney test; *P < .05; **P < .01; ***P < .001.
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