Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Jul 22;7(297):297ra115.
doi: 10.1126/scitranslmed.aac5722.

Human NK cell repertoire diversity reflects immune experience and correlates with viral susceptibility

Dara M Strauss-Albee  1 , Julia Fukuyama  2 , Emily C Liang  3 , Yi Yao  4 , Justin A Jarrell  1 , Alison L Drake  5 , John Kinuthia  6 , Ruth R Montgomery  4 , Grace John-Stewart  7 , Susan Holmes  2 , Catherine A Blish  8
Affiliations

Human NK cell repertoire diversity reflects immune experience and correlates with viral susceptibility

Dara M Strauss-Albee et al. Sci Transl Med. .

Abstract

Innate natural killer (NK) cells are diverse at the single-cell level because of variegated expressions of activating and inhibitory receptors, yet the developmental roots and functional consequences of this diversity remain unknown. Because NK cells are critical for antiviral and antitumor responses, a better understanding of their diversity could lead to an improved ability to harness them therapeutically. We found that NK diversity is lower at birth than in adults. During an antiviral response to either HIV-1 or West Nile virus, NK diversity increases, resulting in terminal differentiation and cytokine production at the cost of cell division and degranulation. In African women matched for HIV-1 exposure risk, high NK diversity is associated with increased risk of HIV-1 acquisition. Existing diversity may therefore decrease the flexibility of the antiviral response. Collectively, the data reveal that human NK diversity is a previously undefined metric of immune history and function that may be clinically useful in forecasting the outcomes of infection and malignancy.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1. Human NK cell repertoire and function are stable for 6 months in an individual, yet can be rapidly mobilized by exogenous factors
(A) NKp30 expression over 6 months in donor HIP11. Time points T1 to T5 occurred weekly within a 6-week period; T6 occurred 6 months later. (B) Stability of the human NK repertoire based on single receptor expression patterns at T1 to T6. Columns represent six blood draws for a single donor; circle size represents frequency of receptor expression. n = 12. (C) Mean SDs of each receptor’s expression over the 6-month period given by Bayesian inference hierarchical model (see Methods for details). Black bars, 95% CrI for mean SD of each receptor for T1 to T6; Healthy Immune Profiling (HIP) donors. Colored dots, mean SD for each donor after in vitro IL-15 (n = 10) or IL-2 (n = 12) stimulation for 72 hours; Stanford Blood Bank (SBB) donors. (D) Up-regulation of NKp30 after 72-hour treatment with IL-15 or IL-2 in donor SBB10. (E) Stability of NK cell function over 6 months. The diagram shows the 95% CrI for mean SD of each function (CD107a, IFN-γ, and TNF) after 721.221 stimulation at T1 to T6. n = 3.
Fig. 2
Fig. 2. NK cell diversity is stable and donor-specific
T1 to T6 box plot [box = median + interquartile range (IQR); whiskers = 1.5 × IQR] distributions of NK diversity (inverse Simpson Index) in HIP donors (n = 12).
Fig. 3
Fig. 3. Diverse NK repertoires contain differentiated NK cells unique to an individual
(A and B) CD57 and (A) NKG2A (B) frequency on NK cells versus NK cell repertoire diversity for HIP donors. Circles, individual time points. Triangles, mean of all time points in each individual. Linear regression, black; 95% CI, gray. Generalized estimating equation, AR-1 correlation structure: CD57, P = 7.8 × 10−3; NKG2A, P = 7.5 × 10−5. n = 12. (C to E) CD57 frequency (C), NKG2A frequency (D), and NK diversity (inverse Simpson index) (E) on umbilical cord bloods (n = 20) versus HIP donors (n = 12). Mann-Whitney U tests: CD57, P = 8.9 × 10−9; NKG2A, P = 3.7 × 10−5; diversity, P = 1.4 × 10−4. (F) Convergence analysis of NK phenotypes. Total proportion of phenotypes expressing CD57 (magenta) or NKG2A (blue) shared at baseline. Linear regression: CD57, P = 5.6 × 10−5; NKG2A, P = 0.031. n = 12, SBB donors.
Fig. 4
Fig. 4. NK cell repertoire diversity correlates with acquisition of HIV-1 in Kenyan women
(A) Distributions of NK cell repertoire diversity (inverse Simpson index) in cases (n = 13) and matched controls (n = 23) (logistic regression odds ratio per 100-point diversity increase, 2.5; 95% CI, 1.2 to 6.2). (B) Box plots of NK receptor diversity on CD4+ T, CD8+ T, and NK cells in cases and controls (logistic regression of diversity versus HIV-1 acquisition for CD4+ and CD8+ T cells is not significant; NK, P = 0.029). (C) Box plots show distributions of expression frequency of each receptor on CD4+ T, CD8+ T, and NK cells in cases versus controls. All case-control receptor comparisons are not significant by logistic regression.
Fig. 5
Fig. 5. Differentiated NK repertoires are skewed toward cytokine production in response to virus-infected cells
(A to D) Frequency of cells producing IFN-γ (A), TNF (B), CD107a (C), and IdU (D) in CD57− or CD57+ NK cells after stimulation with IL-2 and HIV-1–infected target cells. Wilcoxon signed-rank tests: IFN-γ, P = 3.4 × 10−3; TNF, P = 0.021; CD107a, P = 0.027; IdU, P = 0.077. SBB donors, n = 11.
Fig. 6
Fig. 6. Short-term exposure to virus-infected cells augments NK diversity
(A to F) Correspondence analysis of Boolean phenotypes for HIV-1 (A to C, n = 12) or WNV (D to F, n = 33). (A and D) Components 1 and 2 of analysis of all phenotypes after culture with IL-2 alone (HIV-1) or unstimulated (WNV). For HIV-1, 11,523 total phenotypes were detected, and for WNV, 8397 phenotypes. (B and E) Components 1 and 2 and total change in component 3 (colored arrows) after culture with IL-2 + HIV-1–infected CD4+ T cells (B) or after PBMC infection with WNV (E). (C and F) Sum of squared distances to centroid of point cloud in NK cells cultured with IL-2 alone (HIV-1−) or IL-2 + HIV-1–infected CD4+ T cells (HIV-1+) (C) or PBMCs uninfected with WNV (WNV−) or with WNV infection (WNV+) (F). Permutation test (10,000×) on sum of squared distances from centroid: HIV-1, P = 0.038; WNV, P = 1.0 × 10−4. (G and H) Diversity of NK cells cultured with IL-2 alone (HIV-1−) or IL-2 + HIV-1–infected CD4+ T cells (HIV-1+) (G, n = 12) or uninfected with WNV (WNV−) or with WNV infection (WNV+) (H, n = 33); Wilcoxon signed-rank tests: HIV-1, P = 0.034; WNV, P = 0.0033. (I) Model for NK cell diversity and differentiation. A naïve NK repertoire is an effective fence for infection prevention. As the NK repertoire encounters novel pathogens over the course of a lifetime, it diversifies with each response mounted. Its increasingly branched, diffuse nature increases the chance that a newly encountered virus will penetrate the barrier.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Rechavi Ea., Lev A, Lee YN, Simon AJ, Yinon Y, Lipitz S, Amariglio N, Weisz B, Notarangelo LD, Somech R. Timely and spatially regulated maturation of B and T cell repertoire during human fetal development. Sci. Transl. Med. 2015;7:276ra25. - PubMed
    1. Garderet L, Dulphy N, Douay C, Chalumeau N, Schaeffer V, Zilber M-T, Lim A, Even J, Mooney N, Gelin C, Gluckman E, Charron D, Toubert A. The umbilical cord blood αβ T-cell repertoire: Characteristics of a polyclonal and naive but completely formed repertoire. Blood. 1998;91:340–346. - PubMed
    1. Shiokawa S, Mortari F, Lima JO, Nuñez C, Bertrand FE, III, Kirkham PM, Zhu S, Dasanayake AP, Schroeder HW. IgM heavy chain complementarity-determining region 3 diversity is constrained by genetic and somatic mechanisms until two months after birth. J. Immunol. 1999;162:6060–6070. - PubMed
    1. Schroeder HW, Jr., Zhang L, Philips JB., III Slow, programmed maturation of the immunoglobulin HCDR3 repertoire during the third trimester of fetal life. Blood. 2001;98:2745–2751. - PubMed
    1. Horowitz A, Strauss-Albee DM, Leipold M, Kubo J, Nemat-Gorgani N, Dogan OC, Dekker CL, Mackey S, Maecker H, Swan GE, Davis MM, Norman PJ, Guethlein LA, Desai M, Parham P, Blish CA. Genetic and environmental determinants of human NK cell diversity revealed by mass cytometry. Sci. Transl. Med. 2013;5:208ra145. - PMC - PubMed

Publication types