Research Article: BATF3-dependent dendritic cells drive both effector and regulatory T-cell responses in bacterially infected tissues

Date Published: June 12, 2019

Publisher: Public Library of Science

Author(s): Isabelle C. Arnold, Xiaozhou Zhang, Mariela Artola-Boran, Angela Fallegger, Peter Sander, Pål Johansen, Anne Müller, Denise M. Monack.

http://doi.org/10.1371/journal.ppat.1007866

Abstract

The gastric lamina propria of mice that have been experimentally infected with the pathobiont Helicobacter pylori hosts a dense network of myeloid cells that includes BATF3-dependent CD103+ dendritic cells (DCs). We show here that CD103+ DCs are strictly required for gastric Th1 responses to H. pylori and for H. pylori infection control. A similar dependence of type 1 immunity on CD103+ DCs is observed in a Mycobacterium bovis BCG infection model, and in a syngeneic colon cancer model. Strikingly, we find that not only the expansion and/or recruitment of Th1 cells, but also of peripherally induced, neuropilin-negative regulatory T-cells to sites of infection requires BATF3-dependent DCs. A shared feature of the examined models is the strongly reduced production of the chemokines and CXCR3 ligands CXCL9, 10 and 11 in BATF3-deficient mice. The results implicate BATF3-dependent DCs in the recruitment of CXCR3+ effector and regulatory T-cells to target tissues and in their local expansion.

Partial Text

Mononuclear phagocytes (MPs) residing in the lamina propria (LP) of the gastrointestinal (GI) tract comprise populations of resident macrophages that are replenished from Ly6Chi blood monocytes, and of dendritic cells (DCs) that originate from a pre-DC-progenitor and require FLT3L for their development [1, 2]. Three gastrointestinal DC lineages exist in the steady state; these can be identified based on their surface marker expression, dependence on transcription and growth factors, and functional specialization. CD103+CD11b- DCs require the basic leucine zipper transcription factor ATF-like 3 (BATF3) and interferon regulatory factor 8 (IRF8) for their development [3] and are equipped to cross-present viral, tumor, and self-antigens; the functional human equivalent of CD103+CD11b- DCs is the CD141hi DC subset [4]. The development of CD103+CD11b+ DCs depends on granulocyte macrophage colony-stimulating factor (GM-CSF) [5, 6] as well as the transcription factors Notch-2 [7] and IRF4 [8]. Functionally, IRF4/Notch-2-dependent DCs (likely human equivalent: CD1c+ DCs) have been implicated in Th17 priming [7, 8]. The third DC subset of the GI tract expresses CD11b and intermediate levels of CX3CR1, but neither CD103 nor typical macrophage markers such as F4/80, Ly6C, or CD64. This DC population shares the IRF4/Notch-2 dependence of CD103+CD11b+ DCs and is responsive to FLT3L in vivo, but its progenitor is controversial [9–11]. The lymph node counterparts of the described LP DCs are CD11b+ and CD8α+ DCs, which share the reliance on IRF4/Notch-2 and IRF8/BATF3, respectively.

We show here that BATF3-dependent DCs are absolutely required for the Th1-driven control of a mucosal and a systemic bacterial pathogen, H. pylori and M. bovis BCG. Our data are in line with previous evidence for a critical role of BATF3-dependent CD103+ DCs in the activation and expansion of Th1 cells in murine models of Leishmania major infection [32] and in immune protection against the newly identified protist Tritrichomonas musculis that colonizes the murine intestine and triggers strongly Th1-polarized T-cell responses [33]. Our data support a model where BATF3-dependent DCs are dispensable for T-cell priming -as we find Th1 cell frequencies in the MLNs to be relatively normal- but indispensible for Th1 cell recruitment to, and expansion in the target tissue. BATF3-dependent CD103+ DCs of the GI tract are better known for their potency at driving CD8+ T cell immunity [3, 34, 35] and for their role in priming Treg differentiation through the production of retinoic acid [36, 37]. Our data, as well as the results from the Leishmania and Tritrichomonas musculis studies [32], further attribute an essential function in promoting local Th1 responses to this versatile DC subset in the GI tract.

 

Source:

http://doi.org/10.1371/journal.ppat.1007866

 

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