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. 2011 Sep 6;108(36):14725-32.
doi: 10.1073/pnas.1110900108. Epub 2011 Aug 8.

Expansion of a unique CD57⁺NKG2Chi natural killer cell subset during acute human cytomegalovirus infection

Sandra Lopez-Vergès  1 , Jeffrey M Milush, Brian S Schwartz, Marcelo J Pando, Jessica Jarjoura, Vanessa A York, Jeffrey P Houchins, Steve Miller, Sang-Mo Kang, Phillip J Norris, Douglas F Nixon, Lewis L Lanier
Affiliations

Expansion of a unique CD57⁺NKG2Chi natural killer cell subset during acute human cytomegalovirus infection

Sandra Lopez-Vergès et al. Proc Natl Acad Sci U S A. .

Abstract

During human CMV infection, there is a preferential expansion of natural killer (NK) cells expressing the activating CD94-NKG2C receptor complex, implicating this receptor in the recognition of CMV-infected cells. We hypothesized that NK cells expanded in response to pathogens will be marked by expression of CD57, a carbohydrate antigen expressed on highly mature cells within the CD56(dim)CD16(+) NK cell compartment. Here we demonstrate the preferential expansion of a unique subset of NK cells coexpressing the activating CD94-NKG2C receptor and CD57 in CMV(+) donors. These CD57(+)NKG2C(hi) NK cells degranulated in response to stimulation through their NKG2C receptor. Furthermore, CD57(+)NKG2C(hi) NK cells preferentially lack expression of the inhibitory NKG2A receptor and the inhibitory KIR3DL1 receptor in individuals expressing its HLA-Bw4 ligand. Moreover, in solid-organ transplant recipients with active CMV infection, the percentage of CD57(+)NKG2C(hi) NK cells in the total NK cell population preferentially increased. During acute CMV infection, the NKG2C(+) NK cells proliferated, became NKG2C(hi), and finally acquired CD57. Thus, we propose that CD57 might provide a marker of "memory" NK cells that have been expanded in response to infection.

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Conflict of interest statement

Conflict of interest statement: J.P.H. is an employee of R&D Systems. The other authors have no conflicts.

Figures

Fig. 1.
Fig. 1.
A unique population of CD57+NKG2Chi NK cells is detected in CMV+ donors. (A) CD3negCD56dimCD16+ NK cells from four CMV− (Upper) and CMV+ (Lower) donors were gated and analyzed for expression of CD57 and NKG2C. (B) The geometric mean fluorescence intensity (gMFI) for NKG2C in the CD57+ NK cell subset from CMV− and CMV+ donors is shown. (C) The percentage of CD57+NKG2Chi cells in the CD56dimCD16+ NK cell subset from CMV+ and CMV− donors is shown. (D) The ratio of CD57+NKG2Chi/CD57−NKG2Chi NK cells for each CMV− and CMV+ donors is shown. Triangles represent CMV− donors (n = 23), circles represent CMV+ donors (i.e., seropositive and/or CMV-specific T-cell responses; n = 29).
Fig. 2.
Fig. 2.
CD57+NKG2Chi NK cells from CMV+ donors degranulated when activated through NKG2C. PBMCs from CMV+ donors where stimulated with plate-bound antibodies against CD56 (negative control), NKG2C, or CD16 (positive control). The percentage of CD107α+ cells was determined for CD57+NKG2Chi NK cells (n = 7).
Fig. 3.
Fig. 3.
Certain inhibitory NK receptors are underrepresented on the CD57+NKG2Chi NK cell subset from CMV+ donors. (A) CD56dimCD16+ NK cells from CMV− (Left) and CMV+ (Right) donors were gated and analyzed for expression of CD57 and NKG2C. CD57+NKG2C− (a), CD57+NKG2Cdim (b), and CD57+NKG2Chi (c) NK cells were assessed for CD56 and NKG2A expression. (B) The percentage of NKG2A+ cells was determined on CD57+NKG2C− and CD57+NKG2Chi NK cells from CMV+ donors (n = 16). (C) The percentage of KIR3DL1+ cells was determined on CD57+NKG2C− and CD57+NKG2Chi NK cells from CMV+ donors. Graphs from HLA-Bw4+ (Upper; n = 9) and HLA-Bw4− donors (Lower; n = 6) are shown. (D) The percentage of KIR2DL1+ cells was determined on CD57+NKG2C− and CD57+NKG2Chi NK cells for CMV+ donors who have the KIR2DL1 ligand (Left; n = 5) or do not (Right; n = 7).
Fig. 4.
Fig. 4.
CD57+NKG2Chi NK cells increase during acute CMV infection in SOT recipients. (A) NKG2C and CD57 expression on CD56dimCD16+ NK cells from SOT recipients with acute CMV infection was analyzed. Antiviral treatment was administrated immediately after detection of viremia (day 0). The percentage of CD57+NKG2Chi NK cells detected over time and the CMV viral load detected in plasma (value > 400 copies/mL) from representative patients are shown (n = 6). Solid line and square represent CD57+NKG2Chi NK cells, dashed line and triangle represent CMV DNA. (B and C) The percentages of CD57+NKG2Chi NK cells detected over time from one representative SOT recipient without CMV viremia (B; n = 5) and from a healthy CMV+ donor (C) are shown. (D and E) Approximate absolute numbers (in 103 cells/L) of CD57+NKG2Chi NK cells detected over time in one representative SOT recipient with CMV viremia (D; CMV viral load shown; n = 6) and in SOT recipients without CMV viremia (E; n = 5).
Fig. 5.
Fig. 5.
During CMV acute infection, NKG2C+ NK cells acquire CD57 expression and become CD57+NKG2Chi NK cells. (A and B) The percentages of CD57+ NK cells detected over time in SOT recipients with acute CMV infection (A; n = 6) or without CMV viremia (B; n = 5) are shown. (C) CD56dimCD16+ NK cells were analyzed for expression of CD57 and NKG2C. Plots for different time points from a representative SOT recipient with CMV viremia are shown (n = 6). Population gates: CD57−NKG2Cdim, CD57−NKG2Chi, CD57dimNKG2Chi, and CD57+NKG2Chi NK cells. (D) CD56dimCD16+ NK cells were gated on NKG2C+ and NKG2C− cells and the percentage of CD57+ cells for each subset was assessed over time. The ratio of CD57+/CD57− cells on each subset from a representative SOT recipient with CMV viremia is shown (n = 6). Solid square is from NKG2C+, solid triangle is from NKG2C− NK cells.
Fig. 6.
Fig. 6.
All NK cells divide in response to acute CMV infection. (A and B) CD56dimCD16+ NK cells were gated on NKG2C+ and NKG2C− cells, and Ki-67 expression on all CD56dimCD16+ NK cells and in each subset was assessed. Graphs from representative SOT recipients with CMV viremia (A; n = 4) and without CMV viremia (B) are shown. Solid line and empty circle represent CD56dimCD16+ NK cells, solid line and square represent NKG2C+ NK cells, and dashed line and triangle represent NKG2C− NK cells. (C) The percentage of Ki-67+ cells within the CD56dimCD16+ NK cells detected over time in healthy CMV+ donors is shown.
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