マラリア原虫感染におけるCD４＋T細胞のPD-1／LAG-3発現とサイトカイン産生の解析

CD4+ T cells play critical roles in protection against the blood-stage of malaria infection, but their uncontrolled activation can be harmful to the host. We compared the expression of inhibitory receptors on activated CD4+ T cells and their cytokine production using rodent models of Plasmodium parasites, and compared them with those from a bacterial and another protozoan infection. CD4+ T cells from mice infected with P. yoelii 17XL, P yoelii 17XNL, P. chabaudi, P. vinckei, and P. berghei expressed the inhibitory receptors, PD-1 and LAG-3 as early as 6 days after infection, while those from either Listeria monocytogenes or Leishmania major-infected mice did not. In response to T-cell receptor stimulation, CD4+ T cells from mice infected with all the pathogens under study produced high levels of IFN-γ. IL-2 production was reduced in mice infected with Plasmodium species, but not with Listeria or Leishmania. In vitro blockade of the interaction between PD-1 and its ligands resulted in increased IFN-γ production in response to Plasmodium antigens, implying that PD-1 expressed on activated CD4+ T cells actively inhibit T cell immune responses. Studies using Myd88-/-, Trif-/-, and Irf3-/- mice showed that the induction of these CD4+ T cells and their ability to produce cytokines was largely independent of toll-like receptor signaling. These studies suggest that the expression of the inhibitory receptors, PD-1 and LAG-3 on CD4+ T cells and their reduced IL-2 production are common characteristic features of Plasmodium infection.長崎大学学位論文 学位記番号:博(医歯薬)甲第859号 学位授与年月日:平成28年3月18日Author: Henrietta T. Doe, Daisuke Kimura, Mana Miyakoda, Kazumi Kimura, Masoud Akbari, Katsuyuki YuiCitation: Microbiology and Immunology, 60(2), pp.121-131; 201