Distinct and Overlapping Effector Functions of Expanded Human CD4, CD8? and CD4CD8? Invariant Natural Killer T Cells
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2011Citation:
O'Reilly V, Zeng SG, Bricard G, Atzberger A, Hogan AE, Jackson J, Feighery C, Porcelli SA, Doherty DG, Distinct and Overlapping Effector Functions of Expanded Human CD4, CD8? and CD4CD8? Invariant Natural Killer T Cells, PloS one, 6, 12, e28648, 2011Download Item:
Distinct and Overlapping Effector Functions of Expanded Human CD4, CD8? and CD4CD8? Invariant Natural Killer T Cells.pdf (Published (publisher's copy) - Peer Reviewed) 699.9Kb
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(+), CD8?(+) and CD4(-)CD8?(-) double-negative (DN) subsets. CD4(+) iNKT cells expanded more readily than CD8?(+) and DN iNKT cells upon mitogen stimulation. CD8?(+) 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-? and TNF-?) and Th2 (IL-4, IL-5 and IL-13) cytokines. Relative amounts followed a CD8?>DN>CD4 pattern for Th1 and CD4>DN>CD8? for Th2. All iNKT subsets could simultaneously produce IFN-? and IL-4, but single-positivity for IFN-? or IL-4 was strikingly rare in CD4(+) and CD8?(+) 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 CD8?(+), DN or CD4(+) iNKT cells may optimally harness the immunoregulatory properties of iNKT cells for treatment of disease.
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Health Research Board
PHD/2004/2
Science Foundation Ireland
05/RFP/BIC0015
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http://people.tcd.ie/dohertdehttp://people.tcd.ie/atzberga
http://people.tcd.ie/jjackso2
http://people.tcd.ie/cfighery
http://people.tcd.ie/zengsg
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PUBLISHED
Author: ATZBERGER, ANN; JACKSON, JOHN; O'REILLY, VINCENT; DOHERTY, DEREK; FEIGHERY, CONLETH FRANCIS; ZENG, SHIJUAN GRACE
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PloS one;6;
12, e28648;
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Immunology, Invariant Natural Killer T CellsLicences: