McDyer J F, Goletz T J, Thomas E, June C H, Seder R A
Lymphokine Regulation Unit, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
J Immunol. 1998 Feb 15;160(4):1701-7.
CD40 ligand (CD40L)/CD40 costimulation is an important regulator of Th1 responses. Two mechanisms by which CD40L/CD40 stimulation may enhance IFN-gamma are via direct induction of IL-12 and augmentation of the expression of costimulatory molecules such as B7 from APCs. We examined the ability of CD40L/CD40 stimulation to regulate the production of IFN-gamma through IL-12 and/or CD28 costimulation from human PBMCs stimulated with T cell-specific stimuli. The roles of exogenous and endogenous CD40L/CD40 stimulation were evaluated using a trimeric soluble CD40L agonist (CD40T) and an anti-CD40L Ab, respectively. The presence of CD40T in cultures increased the production of IL-12 and IFN-gamma from PBMCs stimulated with varying amounts of PHA. The mechanism, however, by which CD40T enhanced IFN-gamma varied according to the level of T cell activation. Under maximal stimulatory conditions (PHA, 1/100), an IL-12-dependent pathway was dominant. At relatively low levels of T cell stimulation (PHA, 1/500 and 1/1000), however, an additional IL-12-independent CD28-dependent pathway was elucidated. We further studied the role of exogenous CD28 stimulation in regulating the production of IFN-gamma. The enhancement of IFN-gamma production induced by direct CD28 stimulation was primarily dependent on endogenous IL-12 or CD40L/CD40 stimulation. Together, these data suggest that the production of IFN-gamma involves a complex interaction between two interdependent, yet distinct, costimulatory pathways and provide evidence that CD40T may be an effective adjuvant for the enhancement of responses.
CD40配体（CD40L）/CD40共刺激是Th1反应的重要调节因子。CD40L/CD40刺激增强γ干扰素的两种机制是通过直接诱导白细胞介素-12以及增强共刺激分子如抗原呈递细胞（APC）上B7分子的表达。我们研究了CD40L/CD40刺激通过白细胞介素-12和/或来自用T细胞特异性刺激物刺激的人外周血单个核细胞（PBMC）的CD28共刺激来调节γ干扰素产生的能力。分别使用三聚体可溶性CD40L激动剂（CD40T）和抗CD40L抗体评估外源性和内源性CD40L/CD40刺激的作用。培养物中CD40T的存在增加了用不同量PHA刺激的PBMC中白细胞介素-12和γ干扰素的产生。然而，CD40T增强γ干扰素的机制根据T细胞活化水平而有所不同。在最大刺激条件下（PHA，1/100）时，白细胞介素-12依赖性途径占主导。然而，在相对较低水平的T细胞刺激下（PHA，1/500和1/1000），阐明了一条额外的不依赖白细胞介素-12的CD28依赖性途径。我们进一步研究了外源性CD28刺激在调节γ干扰素产生中的作用。直接CD28刺激诱导的γ干扰素产生的增强主要依赖于内源性白细胞介素-12或CD40L/CD40刺激。总之，这些数据表明γ干扰素的产生涉及两条相互依赖但又不同的共刺激途径之间的复杂相互作用，并提供证据表明CD40T可能是增强反应的有效佐剂。
