Effective collaboration between marginal metallophilic macrophages and CD8⁺dendritic cells in the generation of cytotoxic T cells

Abstract

The spleen is the lymphoid organ that induces immune responses toward blood-borne pathogens. Specialized macrophages in the splenic marginal zone are strategically positioned to phagocytose pathogens and cell debris, but are not known to play a role in the activation of T-cell responses. Here we demonstrate that splenic marginal metallophilic macrophages (MMM) are essential for crosspresentation of blood-borne antigens by splenic dendritic cells (DCs). Our data demonstrate that antigens targeted to MMM as well as blood-borne adenoviruses are efficiently captured by MMM and exclusively transferred to splenic CD8 + DCs for cross-presentation and for the activation of cytotoxic T lymphocytes. Depletion of macrophages in the marginal zone prevents cytotoxic T-lymphocyte activation by CD8 + DCs after antibody targeting or adenovirus infection. Moreover, we show that tumor antigen targeting to MMM is very effective as antitumor immunotherapy. Our studies point to an important role for splenic MMM in the initial steps of CD8 + T-cell immunity by capturing and concentrating blood-borne antigens and the transfer to cross-presenting DCs which can be used to design vaccination strategies to induce antitumor cytotoxic T-cell immunity.antigen presentation | infection T he spleen is essential for the induction of immune responses toward blood-borne antigens and has a unique architecture. Arterial blood flow terminates in marginal sinuses situated in the marginal zone (MZ) that surrounds the white pulp containing Bcell follicles and T-cell zones. Marginal sinuses are lined by reticular cells and contain marginal zone B cells and two types of macrophages (Mφ) (1, 2). Marginal metallophilic macrophages (MMM), characterized by the expression of sialic acid-binding Iglike lectin-1 (Siglec-1, Sialoadhesin, CD169) (3, 4), are located as a tight network in the inner part of the MZ near the white pulp, whereas marginal zone macrophages (MZM), which specifically express the C-type lectin SIGN-R1, can be found in the outer MZ toward the red pulp (5). Both MZM and a subset of MMM express the type I scavenger receptor MARCO (6). Although MMM and MZM efficiently take up particulate antigens (Ag) present in the blood (7-9), they are hitherto considered not to be important for the generation of T-cell responses (8-10).In contrast to Mφ, dendritic cells (DCs) are specialized Agpresenting cells that have a dominant role in initiating primary Tcell responses. Murine splenic DCs can be divided into two different subsets based on the expression of phenotypic markers: localization and function (11). CD8 + DCs express the C-type lectin DEC205 and are found in the T-cell zone and the outer marginal zone (12). They are specialized in cross-presentation of Ag and in the activation and tolerization of cytotoxic T cells (CTLs) (13-16). Furthermore, they are important for the generation of antitumor specific immune responses and the elimination of tumors in vivo (17). In contrast, CD8− DCs are specialized in the activation of CD4 + T cells. CD8 − DCs are...

CD8+ T-cell expansion and maintenance after recombinant adenovirus immunization rely upon cooperation between hematopoietic and nonhematopoietic antigen-presenting cells

“…10 A recent report suggested that after intravenous immunization with rHuAd5, marginal metallophilic macrophages capture antigen and transfer it to CD8␣ ϩ DCs. 44 Because we observed that most of the antigen within DLNs was located in CD11b ϩ cells (supplemental Figure 1), macrophages in the subcapsular sinus of the LNs may play a similar role after intramuscular rHuAd5 injection. However, our data suggest that this process would only be important for initial priming and not long-term maintenance.…”

Harnessing Nanoparticles for Immune Modulation

“…Both freely draining and APC-associated NPs arrive in the subcapsular sinus of the lymph node. This region is rich in CD169-expressing macrophages [51], which in the spleen are important for the coordination of CD8+ dendritic cells and their stimulation of effective CD4+ and CD8+ T cell responses against invading pathogens [52]. Subcutaneous delivery of NPs is very effective for stimulating immune responses to numerous T and B cell antigens [50,53].…”

Critical Roles of a Dendritic Cell Subset Expressing a Chemokine Receptor, XCR1

“…CD169 + MZMMFs are known to contribute to cross-presentation of blood-borne Ags by splenic DCs (41). In the LNs, CD169 + cells are found in the sinus and have the ability to cross-present Ags from dead cells (42).…”