Dendritic Cell Migration to Skin-Draining Lymph Nodes Is Controlled by Dermatan Sulfate and Determines Adaptive Immunity Magnitude.

Reza Nadafi,Joke M M Den Haan,Antonie Zwiers,Tanja Konijn,Rogier M Reijmers,Reina E Mebius,Henrike Veninga,Anders Malmström,Jasper J Koning,Xanthi N Stachtea,Marco Maccarana

doi:10.3389/fimmu.2018.00206

Abstract

For full activation of naïve adaptive lymphocytes in skin-draining lymph nodes (LNs), presentation of peptide:MHC complexes by LN-resident and skin-derived dendritic cells (DCs) that encountered antigens (Ags) is an absolute prerequisite. To get to the nearest draining LN upon intradermal immunization, DCs need to migrate from the infection site to the afferent lymphatics, which can only be reached by traversing a collagen-dense network located in the dermis of the skin through the activity of proteolytic enzymes. Here, we show that mice with altered collagen fibrillogenesis resulting in thicker collagen fibers in the skin display a reduced DC migration to the draining LN upon immune challenge. Consequently, the initiation of the cellular and humoral immune response was diminished. Ag-specific CD8+ and CD4+ T cells as well as Ag-specific germinal center B cells and serum immunoglobulin levels were significantly decreased. Hence, we postulate that alterations to the production of extracellular matrix, as seen in various connective tissue disorders, may in the end affect the qualitative outcome of adaptive immunity.

Highlights

Lymph nodes (LNs) are strategically located secondary lymphoid organs that drain most tissues of the body, including the skin as the largest organ, to collect foreign soluble and particulate antigens (Ags) through a lymphatic vasculature [1, 2]
Quantification of single-cell suspensions by flow cytometry of skin-draining LNs (sdLNs) revealed equal total cell numbers, including similar amounts of total dendritic cell (DC), T cells, and B cells, all immune cell subsets critically involved in the initiation of an adaptive immune response (Figure 1A)
Fluorescent immunohistochemistry analysis showed a comparable cellular architecture as to WT lymph node (LN), with B cells organized in follicles lined by subcapsular sinus macrophages, and DCs dispersed throughout the T cell zone (Figure 1B)

Summary

Introduction

Lymph nodes (LNs) are strategically located secondary lymphoid organs that drain most tissues of the body, including the skin as the largest organ, to collect foreign soluble and particulate antigens (Ags) through a lymphatic vasculature [1, 2]. The collection of Ags is essential for a controlled and rapid initiation of a robust and Ag-specific adaptive immune response [2,3,4]. Ag-containing lymph will flow via the afferent vessels into the sinuses and a collagen-rich conduit system of the draining LN, produced by lymphoid stromal cells [5,6,7]. LN-resident dendritic cells (DCs) sample the conduits and sinuses for Ags and present these as peptide:MHC complexes for initial activation of naïve T cells [1, 2]. Newly arriving tissue-resident DCs sequentially present peptide:MHC complexes to Ag-primed naïve T cells, essential for full activation and successive proliferation. When migration of distant DCs was prevented upon rapid removal of the injection site, activation of T cells was significantly diminished and the cellular immunity severely hampered [1, 2]

Methods

Results

Conclusion