Blockade of Costimulation Prevents Infection-Induced Immunopathology in Interleukin-10-Deficient Mice

Interleukin-10 (IL-10) is associated with inhibition of cell-mediated immunity and downregulation of the expression of costimulatory molecules required for T-cell activation. When IL-10-deficient (IL-10KO) mice are infected with Toxoplasma gondii, they succumb to a T-cell-mediated shock-like reaction characterized by the overproduction of IL-12 and gamma interferon (IFN-γ) associated with widespread necrosis of the liver. Since costimulation is critical for T-cell activation, we investigated the role of the CD28-B7 and CD40-CD40 ligand (CD40L) interactions in this infection-induced immunopathology. Our studies show that infection of mice with T. gondii resulted in increased expression of B7 and CD40 that was similar in wild-type and IL-10KO mice. In vivo blockade of the CD28-B7 or CD40-CD40L interactions following infection of IL-10KO mice with T. gondii did not affect serum levels of IFN-γ or IL-12, nor did it prevent death in these mice. However, when both pathways were blocked, the IL-10KO mice survived the acute phase of infection and had reduced serum levels of IFN-γ and alanine transaminase as well as decreased expression of inducible nitric oxide synthase in the liver and spleen. Analysis of parasite-specific recall responses from infected IL-10KO mice revealed that blockade of the CD40-CD40L interaction had minimal effects on cytokine production, whereas blockade of the CD28-B7 interaction resulted in decreased production of IFN-γ but not IL-12. Further reduction of IFN-γ production was observed when both costimulatory pathways were blocked. Together, these results demonstrate that the CD28-B7 and CD40-CD40L interactions are involved in the development of infection-induced immunopathology in the absence of IL-10.

白细胞介素-10（Interleukin-10，IL-10）可抑制细胞介导免疫，并下调T细胞活化所需共刺激分子的表达。当白细胞介素-10基因敲除（IL-10-deficient, IL-10KO）小鼠感染刚地弓形虫（Toxoplasma gondii）时，会发生T细胞介导的休克样反应并死亡，该反应以IL-12与干扰素-γ（gamma interferon, IFN-γ）过度产生为特征，并伴随肝脏广泛坏死。鉴于共刺激通路对T细胞活化至关重要，本研究探究了CD28-B7与CD40-CD40配体（CD40 ligand, CD40L）相互作用在该感染诱导免疫病理中的作用。研究结果显示，感染刚地弓形虫后，野生型与IL-10KO小鼠体内B7与CD40的表达均出现上调，且上调趋势一致。对感染刚地弓形虫的IL-10KO小鼠进行体内CD28-B7或CD40-CD40L通路的阻断，既未影响干扰素-γ与IL-12的血清水平，也未能阻止此类小鼠死亡。然而，当同时阻断这两条共刺激通路时，IL-10KO小鼠可度过感染急性期，其血清中干扰素-γ与丙氨酸转氨酶（alanine transaminase）水平降低，肝脏与脾脏内诱导型一氧化氮合酶（inducible nitric oxide synthase）的表达也显著下降。对感染后IL-10KO小鼠的寄生虫特异性回忆应答分析显示，阻断CD40-CD40L相互作用对细胞因子产生的影响极小，而阻断CD28-B7通路则会导致干扰素-γ产生减少，但不影响IL-12的生成；若同时阻断两条共刺激通路，干扰素-γ的产生会进一步降低。综上，上述结果表明，在缺乏白细胞介素-10的情况下，CD28-B7与CD40-CD40L相互通路参与了感染诱导的免疫病理过程。