Tha-In Thanyalak, Metselaar Herold J, Tilanus Hugo W, Groothuismink Zwier M A, Kuipers Ernst J, de Man Robert A, Kwekkeboom Jaap
Department of Gastroenterology and Hepatology, Erasmus Medical Center-University Medical Center, 3015 CE Rotterdam, The Netherlands.
Blood. 2007 Nov 1;110(9):3253-62. doi: 10.1182/blood-2007-03-077057. Epub 2007 Aug 2.
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.
静脉注射免疫球蛋白（IVIg）发挥免疫调节特性的作用方式广泛且尚未完全明确。IVIg可调节多种免疫细胞的功能，包括抑制树突状细胞（DC）刺激T细胞的能力。在本研究中，我们发现，在IVIg存在下成熟的DC（IVIg-DC）可激活自然杀伤细胞（NK细胞），并增加其γ干扰素的产生和脱颗粒作用。被激活的NK细胞可诱导大多数IVIg-DC发生凋亡。因此，只有在NK细胞存在的情况下，IVIg-DC刺激T细胞的能力才会降低4倍。这是由于NK细胞介导的针对IVIg-DC的抗体依赖性细胞毒性作用（ADCC），可能由IgG多聚体诱导，可通过阻断NK细胞上的CD16来消除。此外，IVIg-DC下调NKp30和杀伤细胞免疫球蛋白样受体（KIR）的表达，并诱导产生CD56（明亮型）CD16（阴性）CCR7（阳性）淋巴结型NK细胞。我们的研究结果确定了一条新途径，即IVIg通过NK细胞诱导成熟DC发生ADCC，从而减少抗原呈递细胞库并抑制T细胞启动。通过影响DC与NK细胞之间的相互作用，IVIg调节先天免疫触发T细胞活化的能力，这是一种在免疫系统激活时可使其“降温”的机制。
