Belkaid Yasmine, Von Stebut Esther, Mendez Susana, Lira Rosalia, Caler Elisabet, Bertholet Sylvie, Udey Mark C, Sacks David
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, and Dermatology Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 2002 Apr 15;168(8):3992-4000. doi: 10.4049/jimmunol.168.8.3992.
Standard murine models of cutaneous leishmaniasis, involving s.c. inoculation of large numbers of Leishmania major promastigotes, have not supported an essential role for CD8(+) T cells in the control of primary infection. Recently, a L. major model combining two main features of natural transmission, low parasite dose and inoculation into a dermal site, has been established in resistant C57BL/6 mice. In the present studies, C57BL/6 mice with CD8(+) T cell deficiencies, including CD8(-/-) and CD8-depleted mice, failed to control the growth of L. major following inoculation of 100 metacyclic promastigotes into the ear dermis. The resulting dermal pathology was minor and delayed. Lesion formation in wild-type mice was coincident with the killing of parasites in the inoculation site. Both events were associated with the accumulation of CD8(+) T lymphocytes in the skin and with the capacity of CD8(+) T cells recovered from draining lymph nodes or infected dermis to release IFN-gamma following coculture with infected dendritic cells. Reconstitution of resistance to L. major in RAG(-/-) mice using T cells from naive donors was optimal when both CD4(+) and CD8(+) T cells were transferred. Primed CD8(+) T lymphocytes obtained from C57BL/6 mice during the acute stage of infection were able to mediate both pathology and immunity when transferred alone. The low dose, intradermal challenge model reveals that CD8(+) T cells play an essential role in both pathogenesis of and immunity to primary infection with L. major in the skin.
皮肤利什曼病的标准小鼠模型，涉及皮下接种大量硕大利什曼原虫前鞭毛体，并未支持CD8(+) T细胞在原发性感染控制中起关键作用。最近，在具有抗性的C57BL/6小鼠中建立了一种结合自然传播两个主要特征的硕大利什曼原虫模型，即低寄生虫剂量和接种到真皮部位。在本研究中，具有CD8(+) T细胞缺陷的C57BL/6小鼠，包括CD8(-/-)小鼠和CD8耗尽的小鼠，在将100个循环前鞭毛体接种到耳部真皮后，无法控制硕大利什曼原虫的生长。由此产生的皮肤病理学变化轻微且延迟。野生型小鼠的病变形成与接种部位寄生虫的杀伤同时发生。这两个事件都与皮肤中CD8(+) T淋巴细胞的积累以及从引流淋巴结或感染真皮中回收的CD8(+) T细胞在与感染的树突状细胞共培养后释放IFN-γ的能力有关。当同时转移CD4(+)和CD8(+) T细胞时，使用来自未免疫供体的T细胞重建RAG(-/-)小鼠对硕大利什曼原虫的抗性最为理想。在感染急性期从C57BL/6小鼠获得的致敏CD8(+) T淋巴细胞单独转移时能够介导病理学变化和免疫反应。低剂量皮内攻击模型表明，CD8(+) T细胞在皮肤中硕大利什曼原虫原发性感染的发病机制和免疫中均起关键作用。
