Dagenais Taylor R, Freeman Bailey E, Demick Karen P, Paulnock Donna M, Mansfield John M
Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA.
J Immunol. 2009 Sep 1;183(5):3344-55. doi: 10.4049/jimmunol.0802005. Epub 2009 Aug 12.
Th1 cell responses to the variant surface glycoprotein (VSG) of African trypanosomes play a critical role in controlling infection through the production of IFN-gamma, but the role of APCs in the induction and regulation of T cell-mediated protection is poorly understood. In this study, we have investigated the Ag presentation capabilities of dendritic cells (DCs) and macrophages during early trypanosome infection in relatively resistant responder and susceptible nonresponder mouse strains. Splenic DCs appeared to be the primary cell responsible for activating naive VSG-specific Th cell responses in resistant responder animals through the coordinated up-regulation of costimulatory molecules, secretion of IL-12, and presentation of VSG peptides to T cells in vivo. Splenic DC depletion and the down-regulation of costimulatory markers on splenic macrophages were observed in susceptible animals and may be associated with the inability of these animals to elicit a significant VSG-specific T cell response. In contrast to splenic APCs, peritoneal macrophages secreted NO, failed to activate naive Th cells in vitro, and presented relatively low levels of VSG peptides to T cells in vivo. Thus, VSG-specific Th1 cell responses may be determined by tissue- and cell-specific differences in Ag presentation. Additionally, all APCs from resistant and susceptible strains displayed a reduced ability to process and present newly encountered exogenous Ag, including new VSG molecules, during high parasitemia. Thus, initial uptake of VSG (or other trypanosome factors) may interfere with Ag presentation and have dramatic consequences for subsequent T cell responses to other proteins.
Th1细胞对非洲锥虫可变表面糖蛋白（VSG）的反应通过产生γ干扰素在控制感染中起关键作用，但抗原呈递细胞（APC）在T细胞介导的保护的诱导和调节中的作用却知之甚少。在本研究中，我们调查了在相对抗性的反应性和易感的无反应性小鼠品系的早期锥虫感染期间树突状细胞（DC）和巨噬细胞的抗原呈递能力。在抗性反应性动物中，脾DC似乎是通过共刺激分子的协同上调、IL-12的分泌以及在体内向T细胞呈递VSG肽来激活幼稚VSG特异性Th细胞反应的主要细胞。在易感动物中观察到脾DC耗竭以及脾巨噬细胞上共刺激标志物的下调，这可能与这些动物无法引发显著的VSG特异性T细胞反应有关。与脾APC相反，腹膜巨噬细胞分泌一氧化氮，在体外不能激活幼稚Th细胞，并且在体内向T细胞呈递相对较低水平的VSG肽。因此，VSG特异性Th1细胞反应可能由抗原呈递中的组织和细胞特异性差异决定。此外，在高寄生虫血症期间，来自抗性和易感品系的所有APC处理和呈递新遇到的外源性抗原（包括新的VSG分子）的能力均降低。因此，VSG（或其他锥虫因子）的初始摄取可能会干扰抗原呈递，并对随后T细胞对其他蛋白质的反应产生重大影响。
