Department of Vascular Biology and Inflammation, CNIC-Fundación Centro Nacional de Investigaciones Cardiovasculares "Carlos III", Madrid, Spain.
Eur J Immunol. 2015 Jan;45(1):119-29. doi: 10.1002/eji.201444651. Epub 2014 Nov 28.
The role of different DC subsets in priming and maintenance of immunity against Leishmania major (L. major) infection is debated. The transcription factor basic leucine zipper transcription factor, ATF-like 3 (Batf3) is essential for the development of mouse CD103(+) DCs and some functions of CD8α(+) DCs. We found that CD103(+) DCs were significantly reduced in the dermis of Batf3-deficient C57BL/6 mice. Batf3(-/-) mice developed exacerbated and unresolved cutaneous pathology following a low dose of intradermal L. major infection in the ear pinnae. Parasite load was increased 1000-fold locally and expanded systemically. Batf3 deficiency did not affect L. major antigen presentation to T cells, which was directly exerted by CD8α(-) conventional DCs (cDCs) in the skin draining LN. However, CD4(+) T-cell differentiation in the LN and skin was skewed to nonprotective Treg- and Th2-cell subtypes. CD103(+) DCs are major IL-12 producers during L. major infection. Local Th1 immunity was severely hindered, correlating with impaired IL-12 production and reduction in CD103(+) DC numbers. Adoptive transfer of WT but not IL-12p40(-/-) Batf3-dependent DCs significantly improved anti-L. major response in infected Batf3(-/-) mice. Our results suggest that IL-12 production by Batf3-dependent CD103(+) DCs is crucial for maintenance of local Th1 immunity against L. major infection.
不同的树突状细胞（DC）亚群在引发和维持对主要组织相容性复合体（MHC）I 类限制的寄生虫感染的免疫反应中的作用存在争议。转录因子碱性亮氨酸拉链转录因子，ATF 样 3（Batf3）对于小鼠 CD103（+）DC 的发育和 CD8α（+）DC 的某些功能至关重要。我们发现，在 Batf3 缺陷型 C57BL/6 小鼠的真皮中，CD103（+）DC 显著减少。Batf3（-/-）小鼠在耳垫皮内接受低剂量的主要组织相容性复合体 I 类限制的寄生虫感染后，皮肤病理表现明显加重且未得到解决。寄生虫负荷在局部增加了 1000 倍，并在全身范围内扩展。Batf3 缺陷并不影响主要组织相容性复合体 I 类限制的寄生虫抗原呈递给 T 细胞，这是由皮肤引流淋巴结中的 CD8α（-）常规 DC（cDC）直接介导的。然而，CD4（+）T 细胞在淋巴结和皮肤中的分化偏向于非保护性调节性 T 细胞（Treg）和 Th2 细胞亚型。在主要组织相容性复合体 I 类限制的寄生虫感染期间，CD103（+）DC 是主要的白细胞介素-12（IL-12）产生者。局部 Th1 免疫受到严重阻碍，这与 IL-12 产生受损和 CD103（+）DC 数量减少有关。WT 而非 IL-12p40（-/-）Batf3 依赖性 DC 的过继转移显著改善了感染 Batf3（-/-）小鼠的抗主要组织相容性复合体 I 类限制的寄生虫反应。我们的结果表明，Batf3 依赖性 CD103（+）DC 产生的白细胞介素-12 对于维持针对主要组织相容性复合体 I 类限制的寄生虫感染的局部 Th1 免疫至关重要。
