Costimulatory signals are required for optimal proliferation of human natural killer cells

Michael Robertson, Thomas J. Manley, Christopher Donahue, Herbert Levine, Jerome Ritz

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

CD56dim NK cells, which comprise ∼90% of human peripheral blood NK cells, respond to IL-2 with cytokine production, up-regulation of functionally relevant surface molecules, and augmented cytolytic activity. Nevertheless, CD56dim NK cells proliferate poorly in response to IL-2 alone. We found that other NK cell mitogens, including IL-4, IL-7, and IL-12, also induced little proliferation of CD56dim NK cells. Indeed, IL-2 stimulated at least 10-fold more NK cell proliferation than did IL-4, IL-7, or IL-12. In contrast, leukocyte-conditioned medium (LCM) induced two- to threefold greater proliferation of CD56dim NK cells than did optimal concentrations of IL-2. Although the calcium ionophore ionomycin did not stimulate proliferation by itself, it markedly augmented LCM-induced proliferation of CD56dim NK cells. Proliferation in response to either LCM alone or LCM together with ionomycin was almost completely abrogated by anti-IL-2R antibodies. Thus, IL-2 appears to be necessary but not sufficient for optimal proliferation of CD56dim NK cells. LCM-induced proliferation of ionomycin-activated CD56dim NK cells was inhibited 24% by anti-IL-1 heteroantisera and 57% by anti-TNF antisera; a combination of both antisera inhibited proliferation by 73%. Furthermore, although rIL-1 and TNF did not induce proliferation by themselves, both cytokines could augment IL-2-induced proliferation of resting or ionomycin-activated NK cells. Hence IL-1 and TNF do not appear to be primary NK cell mitogens, but rather accessory factors that can enhance IL-2-dependent NK cell proliferation. Stimulation through CD2 or CD16 Ag did not enhance LCM-induced NK cell proliferation. However, stimulation with NK-sensitive K562 cells strongly augmented CD56dim NK cell proliferation to LCM or to IL-2, IL-1, and TNF in combination. NK-resistant Daudi cells did not promote the proliferation of highly purified NK cells. Thus, NK cell proliferation may be enhanced by triggering through putative receptors for natural killing, and ionomycin may mimic such triggering. Although IL-2 by itself can induce NK cell proliferation, most NK cells resemble T and B lymphocytes in that they require multiple signals for optimal proliferation.

Original languageEnglish (US)
Pages (from-to)1705-1714
Number of pages10
JournalJournal of Immunology
Volume150
Issue number5
StatePublished - 1993
Externally publishedYes

Fingerprint

Natural Killer Cells
Interleukin-2
Conditioned Culture Medium
Ionomycin
Leukocytes
Cell Proliferation
Interleukin-1
Interleukin-7
Interleukin-12
Mitogens
Interleukin-4
Immune Sera
Cytokines
K562 Cells
Calcium Ionophores

ASJC Scopus subject areas

  • Immunology

Cite this

Robertson, M., Manley, T. J., Donahue, C., Levine, H., & Ritz, J. (1993). Costimulatory signals are required for optimal proliferation of human natural killer cells. Journal of Immunology, 150(5), 1705-1714.

Costimulatory signals are required for optimal proliferation of human natural killer cells. / Robertson, Michael; Manley, Thomas J.; Donahue, Christopher; Levine, Herbert; Ritz, Jerome.

In: Journal of Immunology, Vol. 150, No. 5, 1993, p. 1705-1714.

Research output: Contribution to journalArticle

Robertson, M, Manley, TJ, Donahue, C, Levine, H & Ritz, J 1993, 'Costimulatory signals are required for optimal proliferation of human natural killer cells', Journal of Immunology, vol. 150, no. 5, pp. 1705-1714.
Robertson, Michael ; Manley, Thomas J. ; Donahue, Christopher ; Levine, Herbert ; Ritz, Jerome. / Costimulatory signals are required for optimal proliferation of human natural killer cells. In: Journal of Immunology. 1993 ; Vol. 150, No. 5. pp. 1705-1714.
@article{0da40ce1806549d4bdc2a99f868dc64c,
title = "Costimulatory signals are required for optimal proliferation of human natural killer cells",
abstract = "CD56dim NK cells, which comprise ∼90{\%} of human peripheral blood NK cells, respond to IL-2 with cytokine production, up-regulation of functionally relevant surface molecules, and augmented cytolytic activity. Nevertheless, CD56dim NK cells proliferate poorly in response to IL-2 alone. We found that other NK cell mitogens, including IL-4, IL-7, and IL-12, also induced little proliferation of CD56dim NK cells. Indeed, IL-2 stimulated at least 10-fold more NK cell proliferation than did IL-4, IL-7, or IL-12. In contrast, leukocyte-conditioned medium (LCM) induced two- to threefold greater proliferation of CD56dim NK cells than did optimal concentrations of IL-2. Although the calcium ionophore ionomycin did not stimulate proliferation by itself, it markedly augmented LCM-induced proliferation of CD56dim NK cells. Proliferation in response to either LCM alone or LCM together with ionomycin was almost completely abrogated by anti-IL-2R antibodies. Thus, IL-2 appears to be necessary but not sufficient for optimal proliferation of CD56dim NK cells. LCM-induced proliferation of ionomycin-activated CD56dim NK cells was inhibited 24{\%} by anti-IL-1 heteroantisera and 57{\%} by anti-TNF antisera; a combination of both antisera inhibited proliferation by 73{\%}. Furthermore, although rIL-1 and TNF did not induce proliferation by themselves, both cytokines could augment IL-2-induced proliferation of resting or ionomycin-activated NK cells. Hence IL-1 and TNF do not appear to be primary NK cell mitogens, but rather accessory factors that can enhance IL-2-dependent NK cell proliferation. Stimulation through CD2 or CD16 Ag did not enhance LCM-induced NK cell proliferation. However, stimulation with NK-sensitive K562 cells strongly augmented CD56dim NK cell proliferation to LCM or to IL-2, IL-1, and TNF in combination. NK-resistant Daudi cells did not promote the proliferation of highly purified NK cells. Thus, NK cell proliferation may be enhanced by triggering through putative receptors for natural killing, and ionomycin may mimic such triggering. Although IL-2 by itself can induce NK cell proliferation, most NK cells resemble T and B lymphocytes in that they require multiple signals for optimal proliferation.",
author = "Michael Robertson and Manley, {Thomas J.} and Christopher Donahue and Herbert Levine and Jerome Ritz",
year = "1993",
language = "English (US)",
volume = "150",
pages = "1705--1714",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "5",

}

TY - JOUR

T1 - Costimulatory signals are required for optimal proliferation of human natural killer cells

AU - Robertson, Michael

AU - Manley, Thomas J.

AU - Donahue, Christopher

AU - Levine, Herbert

AU - Ritz, Jerome

PY - 1993

Y1 - 1993

N2 - CD56dim NK cells, which comprise ∼90% of human peripheral blood NK cells, respond to IL-2 with cytokine production, up-regulation of functionally relevant surface molecules, and augmented cytolytic activity. Nevertheless, CD56dim NK cells proliferate poorly in response to IL-2 alone. We found that other NK cell mitogens, including IL-4, IL-7, and IL-12, also induced little proliferation of CD56dim NK cells. Indeed, IL-2 stimulated at least 10-fold more NK cell proliferation than did IL-4, IL-7, or IL-12. In contrast, leukocyte-conditioned medium (LCM) induced two- to threefold greater proliferation of CD56dim NK cells than did optimal concentrations of IL-2. Although the calcium ionophore ionomycin did not stimulate proliferation by itself, it markedly augmented LCM-induced proliferation of CD56dim NK cells. Proliferation in response to either LCM alone or LCM together with ionomycin was almost completely abrogated by anti-IL-2R antibodies. Thus, IL-2 appears to be necessary but not sufficient for optimal proliferation of CD56dim NK cells. LCM-induced proliferation of ionomycin-activated CD56dim NK cells was inhibited 24% by anti-IL-1 heteroantisera and 57% by anti-TNF antisera; a combination of both antisera inhibited proliferation by 73%. Furthermore, although rIL-1 and TNF did not induce proliferation by themselves, both cytokines could augment IL-2-induced proliferation of resting or ionomycin-activated NK cells. Hence IL-1 and TNF do not appear to be primary NK cell mitogens, but rather accessory factors that can enhance IL-2-dependent NK cell proliferation. Stimulation through CD2 or CD16 Ag did not enhance LCM-induced NK cell proliferation. However, stimulation with NK-sensitive K562 cells strongly augmented CD56dim NK cell proliferation to LCM or to IL-2, IL-1, and TNF in combination. NK-resistant Daudi cells did not promote the proliferation of highly purified NK cells. Thus, NK cell proliferation may be enhanced by triggering through putative receptors for natural killing, and ionomycin may mimic such triggering. Although IL-2 by itself can induce NK cell proliferation, most NK cells resemble T and B lymphocytes in that they require multiple signals for optimal proliferation.

AB - CD56dim NK cells, which comprise ∼90% of human peripheral blood NK cells, respond to IL-2 with cytokine production, up-regulation of functionally relevant surface molecules, and augmented cytolytic activity. Nevertheless, CD56dim NK cells proliferate poorly in response to IL-2 alone. We found that other NK cell mitogens, including IL-4, IL-7, and IL-12, also induced little proliferation of CD56dim NK cells. Indeed, IL-2 stimulated at least 10-fold more NK cell proliferation than did IL-4, IL-7, or IL-12. In contrast, leukocyte-conditioned medium (LCM) induced two- to threefold greater proliferation of CD56dim NK cells than did optimal concentrations of IL-2. Although the calcium ionophore ionomycin did not stimulate proliferation by itself, it markedly augmented LCM-induced proliferation of CD56dim NK cells. Proliferation in response to either LCM alone or LCM together with ionomycin was almost completely abrogated by anti-IL-2R antibodies. Thus, IL-2 appears to be necessary but not sufficient for optimal proliferation of CD56dim NK cells. LCM-induced proliferation of ionomycin-activated CD56dim NK cells was inhibited 24% by anti-IL-1 heteroantisera and 57% by anti-TNF antisera; a combination of both antisera inhibited proliferation by 73%. Furthermore, although rIL-1 and TNF did not induce proliferation by themselves, both cytokines could augment IL-2-induced proliferation of resting or ionomycin-activated NK cells. Hence IL-1 and TNF do not appear to be primary NK cell mitogens, but rather accessory factors that can enhance IL-2-dependent NK cell proliferation. Stimulation through CD2 or CD16 Ag did not enhance LCM-induced NK cell proliferation. However, stimulation with NK-sensitive K562 cells strongly augmented CD56dim NK cell proliferation to LCM or to IL-2, IL-1, and TNF in combination. NK-resistant Daudi cells did not promote the proliferation of highly purified NK cells. Thus, NK cell proliferation may be enhanced by triggering through putative receptors for natural killing, and ionomycin may mimic such triggering. Although IL-2 by itself can induce NK cell proliferation, most NK cells resemble T and B lymphocytes in that they require multiple signals for optimal proliferation.

UR - http://www.scopus.com/inward/record.url?scp=0027158409&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027158409&partnerID=8YFLogxK

M3 - Article

VL - 150

SP - 1705

EP - 1714

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 5

ER -