Villegas Eric N, Lieberman Linda A, Mason Nicola, Blass Sarah L, Zediak Valerie P, Peach Robert, Horan Tom, Yoshinaga Steve, Hunter Christopher A
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
J Immunol. 2002 Jul 15;169(2):937-43. doi: 10.4049/jimmunol.169.2.937.
Long-term resistance to Toxoplasma gondii is dependent on the development of parasite-specific T cells that produce IFN-gamma. CD28 is a costimulatory molecule important for optimal activation of T cells, but CD28(-/-) mice are resistant to T. gondii, demonstrating that CD28-independent mechanisms regulate T cell responses during toxoplasmosis. The identification of the B7-related protein 1/inducible costimulator protein (ICOS) pathway and its ability to regulate the production of IFN-gamma suggested that this pathway may be involved in the CD28-independent activation of T cells required for resistance to T. gondii. In support of this hypothesis, infection of wild-type or CD28(-/-) mice with T. gondii resulted in the increased expression of ICOS by activated CD4(+) and CD8(+) T cells. In addition, both costimulatory pathways contributed to the in vitro production of IFN-gamma by parasite-specific T cells and when both pathways were blocked, there was an additive effect that resulted in almost complete inhibition of IFN-gamma production. Although in vivo blockade of the ICOS costimulatory pathway did not result in the early mortality of wild-type mice infected with T. gondii, it did lead to increased susceptibility of CD28(-/-) mice to T. gondi associated with reduced serum levels of IFN-gamma, increased parasite burden, and increased mortality compared with the control group. Together, these results identify a critical role for ICOS in the protective Th1-type response required for resistance to T. gondii and suggest that ICOS and CD28 are parallel costimulatory pathways, either of which is sufficient to mediate resistance to this intracellular pathogen.
对刚地弓形虫的长期抵抗力取决于产生γ干扰素的寄生虫特异性T细胞的发育。CD28是一种对T细胞最佳激活很重要的共刺激分子，但CD28基因敲除小鼠对刚地弓形虫具有抗性，这表明不依赖CD28的机制在弓形虫病期间调节T细胞反应。B7相关蛋白1/诱导性共刺激蛋白（ICOS）途径的鉴定及其调节γ干扰素产生的能力表明，该途径可能参与了抵抗刚地弓形虫所需的T细胞不依赖CD28的激活。支持这一假设的是，用刚地弓形虫感染野生型或CD28基因敲除小鼠会导致活化的CD4⁺和CD8⁺T细胞中ICOS表达增加。此外，这两种共刺激途径都有助于寄生虫特异性T细胞在体外产生γ干扰素，当两种途径都被阻断时，会产生累加效应，几乎完全抑制γ干扰素的产生。虽然在体内阻断ICOS共刺激途径并没有导致感染刚地弓形虫的野生型小鼠早期死亡，但它确实导致CD28基因敲除小鼠对刚地弓形虫的易感性增加，与对照组相比，血清γ干扰素水平降低、寄生虫负荷增加且死亡率升高。总之，这些结果确定了ICOS在抵抗刚地弓形虫所需的保护性Th1型反应中的关键作用，并表明ICOS和CD28是平行的共刺激途径，其中任何一条都足以介导对这种细胞内病原体的抗性。
