Intravenous immunoglobulins suppress T-cell priming by modulating the bidirectional interaction between dendritic cells and natural killer cells.
The modes of action of intravenous immunoglobulins (IVIgs) in exerting their immunomodulatory properties are broad and not fully understood. IVIgs can modulate the function of various immune cells, including suppressing the capacity of dendritic cells (DCs) to stimulate T cells. In the present study, we showed that DCs matured in the presence of IVIgs (IVIg-DCs) activated NK cells, and increased their interferon-gamma production and degranulation. The activated NK cells induced apoptosis of the majority of IVIg-DCs. In consequence, only in the presence of NK cells, IVIg-DCs were 4-fold impaired in their T-cell priming capacity. This was due to NK-cell-mediated antibody-dependent cellular cytotoxicity (ADCC) to IVIg-DCs, probably induced by IgG multimers, which could be abrogated by blockade of CD16 on NK cells. Furthermore, IVIg-DCs down-regulated the expression of NKp30 and KIR receptors, and induced the generation of CD56(bright)CD16(-)CCR7(+) lymph node-type NK cells. Our results identify a novel pathway, in which IVIgs induce ADCC of mature DCs by NK cells, which downsizes the antigen-presenting pool and inhibits T-cell priming. By influencing the interaction between DCs and NK cells, IVIgs modulate the ability of the innate immunity to trigger T-cell activation, a mechanism that can "cool down" the immune system at times of activation.
Department of Gastroenterology and Hepatology, Erasmus Medical Center-University Medical Center, 3015 CE Rotterdam, The Netherlands.
Thanyalak
T
Tha-In
Herold J
HJ
Metselaar
Hugo W
HW
Tilanus
Zwier M A
ZM
Groothuismink
Ernst J
EJ
Kuipers
Robert A
RA
de Man
Jaap
J
Kwekkeboom
D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D019002:CD56 Antigen / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects*; D015550:Cell Degranulation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects*; D054400:Receptors, CCR7 / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects*
C515370:CCR7 protein, human; D019002:CD56 Antigen; C515187:CXCR3 protein, human; D016756:Immunoglobulins, Intravenous; D054400:Receptors, CCR7; D054367:Receptors, CXCR3; D007371:Interferon-gamma