Distinct and overlapping effector functions of expanded human CD4 +, cd8α + and CD4 -CD8α - invariant natural killer T cells

Vincent O'Reilly, Shijuan G. Zeng, Gabriel Bricard, Ann Atzberger, Andrew E. Hogan, John Jackson, Conleth Feighery, Steven A. Porcelli, Derek G. Doherty

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

CD1d-restricted invariant natural killer T (iNKT) cells have diverse immune stimulatory/regulatory activities through their ability to release cytokines and to kill or transactivate other cells. Activation of iNKT cells can protect against multiple diseases in mice but clinical trials in humans have had limited impact. Clinical studies to date have targeted polyclonal mixtures of iNKT cells and we proposed that their subset compositions will influence therapeutic outcomes. We sorted and expanded iNKT cells from healthy donors and compared the phenotypes, cytotoxic activities and cytokine profiles of the CD4 +, CD8α + and CD4 -CD8α - double-negative (DN) subsets. CD4 + iNKT cells expanded more readily than CD8α + and DN iNKT cells upon mitogen stimulation. CD8α + and DN iNKT cells most frequently expressed CD56, CD161 and NKG2D and most potently killed CD1d + cell lines and primary leukemia cells. All iNKT subsets released Th1 (IFN-γ and TNF-α) and Th2 (IL-4, IL-5 and IL-13) cytokines. Relative amounts followed a CD8α&DN&CD4 pattern for Th1 and CD4&DN&CD8α for Th2. All iNKT subsets could simultaneously produce IFN-γ and IL-4, but single-positivity for IFN-γ or IL-4 was strikingly rare in CD4 + and CD8α + fractions, respectively. Only CD4 + iNKT cells produced IL-9 and IL-10; DN cells released IL-17; and none produced IL-22. All iNKT subsets upregulated CD40L upon glycolipid stimulation and induced IL-10 and IL-12 secretion by dendritic cells. Thus, subset composition of iNKT cells is a major determinant of function. Use of enriched CD8α +, DN or CD4 + iNKT cells may optimally harness the immunoregulatory properties of iNKT cells for treatment of disease.

Original languageEnglish (US)
Article numbere28648
JournalPLoS One
Volume6
Issue number12
DOIs
StatePublished - 2011

Fingerprint

Natural Killer T-Cells
T-cells
natural killer cells
T-lymphocytes
interleukin-4
Interleukin-4
cytokines
Cytokines
interleukin-10
Interleukin-10
clinical trials
interleukin-9
Interleukin-9
interleukin-5
harness
CD40 Ligand
Interleukin-13
Interleukin-17
glycolipids
interleukin-12

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

O'Reilly, V., Zeng, S. G., Bricard, G., Atzberger, A., Hogan, A. E., Jackson, J., ... Doherty, D. G. (2011). Distinct and overlapping effector functions of expanded human CD4 +, cd8α + and CD4 -CD8α - invariant natural killer T cells. PLoS One, 6(12), [e28648]. https://doi.org/10.1371/journal.pone.0028648

Distinct and overlapping effector functions of expanded human CD4 +, cd8α + and CD4 -CD8α - invariant natural killer T cells. / O'Reilly, Vincent; Zeng, Shijuan G.; Bricard, Gabriel; Atzberger, Ann; Hogan, Andrew E.; Jackson, John; Feighery, Conleth; Porcelli, Steven A.; Doherty, Derek G.

In: PLoS One, Vol. 6, No. 12, e28648, 2011.

Research output: Contribution to journalArticle

O'Reilly, V, Zeng, SG, Bricard, G, Atzberger, A, Hogan, AE, Jackson, J, Feighery, C, Porcelli, SA & Doherty, DG 2011, 'Distinct and overlapping effector functions of expanded human CD4 +, cd8α + and CD4 -CD8α - invariant natural killer T cells', PLoS One, vol. 6, no. 12, e28648. https://doi.org/10.1371/journal.pone.0028648
O'Reilly, Vincent ; Zeng, Shijuan G. ; Bricard, Gabriel ; Atzberger, Ann ; Hogan, Andrew E. ; Jackson, John ; Feighery, Conleth ; Porcelli, Steven A. ; Doherty, Derek G. / Distinct and overlapping effector functions of expanded human CD4 +, cd8α + and CD4 -CD8α - invariant natural killer T cells. In: PLoS One. 2011 ; Vol. 6, No. 12.
@article{44d6dd44abba4c8b898bb27ab45c3300,
title = "Distinct and overlapping effector functions of expanded human CD4 +, cd8α + and CD4 -CD8α - invariant natural killer T cells",
abstract = "CD1d-restricted invariant natural killer T (iNKT) cells have diverse immune stimulatory/regulatory activities through their ability to release cytokines and to kill or transactivate other cells. Activation of iNKT cells can protect against multiple diseases in mice but clinical trials in humans have had limited impact. Clinical studies to date have targeted polyclonal mixtures of iNKT cells and we proposed that their subset compositions will influence therapeutic outcomes. We sorted and expanded iNKT cells from healthy donors and compared the phenotypes, cytotoxic activities and cytokine profiles of the CD4 +, CD8α + and CD4 -CD8α - double-negative (DN) subsets. CD4 + iNKT cells expanded more readily than CD8α + and DN iNKT cells upon mitogen stimulation. CD8α + and DN iNKT cells most frequently expressed CD56, CD161 and NKG2D and most potently killed CD1d + cell lines and primary leukemia cells. All iNKT subsets released Th1 (IFN-γ and TNF-α) and Th2 (IL-4, IL-5 and IL-13) cytokines. Relative amounts followed a CD8α&DN&CD4 pattern for Th1 and CD4&DN&CD8α for Th2. All iNKT subsets could simultaneously produce IFN-γ and IL-4, but single-positivity for IFN-γ or IL-4 was strikingly rare in CD4 + and CD8α + fractions, respectively. Only CD4 + iNKT cells produced IL-9 and IL-10; DN cells released IL-17; and none produced IL-22. All iNKT subsets upregulated CD40L upon glycolipid stimulation and induced IL-10 and IL-12 secretion by dendritic cells. Thus, subset composition of iNKT cells is a major determinant of function. Use of enriched CD8α +, DN or CD4 + iNKT cells may optimally harness the immunoregulatory properties of iNKT cells for treatment of disease.",
author = "Vincent O'Reilly and Zeng, {Shijuan G.} and Gabriel Bricard and Ann Atzberger and Hogan, {Andrew E.} and John Jackson and Conleth Feighery and Porcelli, {Steven A.} and Doherty, {Derek G.}",
year = "2011",
doi = "10.1371/journal.pone.0028648",
language = "English (US)",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "12",

}

TY - JOUR

T1 - Distinct and overlapping effector functions of expanded human CD4 +, cd8α + and CD4 -CD8α - invariant natural killer T cells

AU - O'Reilly, Vincent

AU - Zeng, Shijuan G.

AU - Bricard, Gabriel

AU - Atzberger, Ann

AU - Hogan, Andrew E.

AU - Jackson, John

AU - Feighery, Conleth

AU - Porcelli, Steven A.

AU - Doherty, Derek G.

PY - 2011

Y1 - 2011

N2 - CD1d-restricted invariant natural killer T (iNKT) cells have diverse immune stimulatory/regulatory activities through their ability to release cytokines and to kill or transactivate other cells. Activation of iNKT cells can protect against multiple diseases in mice but clinical trials in humans have had limited impact. Clinical studies to date have targeted polyclonal mixtures of iNKT cells and we proposed that their subset compositions will influence therapeutic outcomes. We sorted and expanded iNKT cells from healthy donors and compared the phenotypes, cytotoxic activities and cytokine profiles of the CD4 +, CD8α + and CD4 -CD8α - double-negative (DN) subsets. CD4 + iNKT cells expanded more readily than CD8α + and DN iNKT cells upon mitogen stimulation. CD8α + and DN iNKT cells most frequently expressed CD56, CD161 and NKG2D and most potently killed CD1d + cell lines and primary leukemia cells. All iNKT subsets released Th1 (IFN-γ and TNF-α) and Th2 (IL-4, IL-5 and IL-13) cytokines. Relative amounts followed a CD8α&DN&CD4 pattern for Th1 and CD4&DN&CD8α for Th2. All iNKT subsets could simultaneously produce IFN-γ and IL-4, but single-positivity for IFN-γ or IL-4 was strikingly rare in CD4 + and CD8α + fractions, respectively. Only CD4 + iNKT cells produced IL-9 and IL-10; DN cells released IL-17; and none produced IL-22. All iNKT subsets upregulated CD40L upon glycolipid stimulation and induced IL-10 and IL-12 secretion by dendritic cells. Thus, subset composition of iNKT cells is a major determinant of function. Use of enriched CD8α +, DN or CD4 + iNKT cells may optimally harness the immunoregulatory properties of iNKT cells for treatment of disease.

AB - CD1d-restricted invariant natural killer T (iNKT) cells have diverse immune stimulatory/regulatory activities through their ability to release cytokines and to kill or transactivate other cells. Activation of iNKT cells can protect against multiple diseases in mice but clinical trials in humans have had limited impact. Clinical studies to date have targeted polyclonal mixtures of iNKT cells and we proposed that their subset compositions will influence therapeutic outcomes. We sorted and expanded iNKT cells from healthy donors and compared the phenotypes, cytotoxic activities and cytokine profiles of the CD4 +, CD8α + and CD4 -CD8α - double-negative (DN) subsets. CD4 + iNKT cells expanded more readily than CD8α + and DN iNKT cells upon mitogen stimulation. CD8α + and DN iNKT cells most frequently expressed CD56, CD161 and NKG2D and most potently killed CD1d + cell lines and primary leukemia cells. All iNKT subsets released Th1 (IFN-γ and TNF-α) and Th2 (IL-4, IL-5 and IL-13) cytokines. Relative amounts followed a CD8α&DN&CD4 pattern for Th1 and CD4&DN&CD8α for Th2. All iNKT subsets could simultaneously produce IFN-γ and IL-4, but single-positivity for IFN-γ or IL-4 was strikingly rare in CD4 + and CD8α + fractions, respectively. Only CD4 + iNKT cells produced IL-9 and IL-10; DN cells released IL-17; and none produced IL-22. All iNKT subsets upregulated CD40L upon glycolipid stimulation and induced IL-10 and IL-12 secretion by dendritic cells. Thus, subset composition of iNKT cells is a major determinant of function. Use of enriched CD8α +, DN or CD4 + iNKT cells may optimally harness the immunoregulatory properties of iNKT cells for treatment of disease.

UR - http://www.scopus.com/inward/record.url?scp=83155164561&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=83155164561&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0028648

DO - 10.1371/journal.pone.0028648

M3 - Article

C2 - 22174854

AN - SCOPUS:83155164561

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 12

M1 - e28648

ER -