CD169⁺macrophages are sufficient for priming of CTLs with specificities left out by cross-priming dendritic cells

Abstract

Dendritic cells (DCs) are considered the most potent antigen-presenting cells (APCs), which directly prime or cross-prime MHC I-restricted cytotoxic T cells (CTLs). However, recent evidence suggests the existence of other, as-yet unidentified APCs also able to prime T cells. To identify those APCs, we used adenoviral (rAd) vectors, which do not infect DCs but selectively accumulate in CD169 + macrophages (MPs). In mice that lack DCs, infection of CD169 + MPs was sufficient to prime CTLs specific for all epitopes tested. In contrast, CTL responses relying exclusively on cross-presenting DCs were biased to selected strong MHC I-binding peptides only. When both DCs and MPs were absent, no CTL responses could be elicited. Therefore, CD169+ MPs can be considered APCs that significantly contribute to CTL responses. + T cells (4). In contrast, MPs are considered cells of the innate immune system that limit pathogen spread by phagocytosis and degradation. They are positioned at strategically important entry points, such as the subcapsular sinus of lymph nodes and the marginal zone and red pulp areas of the spleen, where they capture and filter pathogens (5). Along with producing type I IFN (6), CD169+ marginal zone metallophilic MPs allow restricted replication of captured virus to increase the local availability of viral Ag (7) for transfer to B cells for humoral responses (8) and to DCs for cross-priming of CD8 + T cells (9). Participation of MPs in T-cell priming is thought to be restricted to Ag acquisition, amplification, and redistribution.Analyzing MP functions in vivo is difficult; genetic models, such as the CD11c-diphteria toxin (DT) receptor (DTR) transgenic mice (2), cannot make the distinction, because both DCs and monocytes/MPs are equally deleted on DT treatment (10, 11). Recent results with mice lacking CD169 + MPs suggest the role of these MPs in cross-priming of CD8 + T cells specific for the cell-associated model Ag ovalbumin (OVA) in lymph nodes (12). These findings are in contrast with another study in which MPs were unable to cross-present soluble OVA protein in mice lacking DCs (11). Although cross-presentation by DCs is now thought to allow priming of cytotoxic T-cell responses to exogenous tumor or viral Ag (4), the importance of cross-presentation in vivo has been a matter of intense debate over the last decade (13). Although this debate remains unresolved, cross-presentation has been considered then and now to be an exception rather than a rule (14,15).To determine the roles of MPs and DCs, we used a mouse model that specifically lacks DCs but conserves all subpopulations of MPs. We show that the presence of directly infected CD169 + MPs is sufficient to prime CTLs, including those recognizing epitopes not covered by cross-presenting DCs. In contrast, when only DCs cross-prime CTLs without the participation of MPs, the CTL repertoire is incomplete and biased toward the few peptides that interact strongly with MHCI. Our data demonstrate a division of labor between CD169 + MPs and DCs in situati...

CIITA-driven MHC class II expressing tumor cells can efficiently prime naive CD4+TH cellsin vivoand vaccinate the host against parental MHC-II-negative tumor cells

“…Moreover, although it has been reported that DT treatment of CD11c. DTR transgenic mice may also partially ablate macrophages, 20,21 the other important professional APC in vivo, we treated CD11c.DTR transgenic mice with LClo, a compound that upon selective phagocytosis by macrophages kills the cells by apoptosis, 19 and in the spleen ablates particularly the marginal zone macrophages and metallophilic macrophages, considered the predominant APCs, in the spleen. 22 Again, upon injection, CIITA-tumor cells could be rejected or strongly retarded in their growth with superimposable behavior as the one observed in liposomal-untreated mice.…”

Dendritic Cells Are Dispensable for T Cell Priming and Control of Acute Lymphocytic Choriomeningitis Virus Infection

“…Exogenous application of DT in CD11c-DTR mice efficiently depletes DCs but also causes depletion of the marginal zone metallophilic macrophages (11,12), which are important to prevent spread of LCMV and T cell exhaustion (13). In contrast, the intrinsic DTA expression in DCs of DDC mice causes selective deletion of classical DCs, plasmacytoid DCs, and Langerhans cells, but not macrophages (12,14).Therefore, DDC mice can be regarded as a more specific model to study the role of DCs for the immune response to LCMV.…”

“…In contrast, diphtheria toxin (DT)-induced ablation of DCs in CD11c-DTR mice resulted in an impaired CD8 T cell response to LCMV (10). However, these results were not conclusive because later studies showed that DT treatment also ablated marginal zone metallophilic macrophages in the spleen (11,12). These macrophages were found to be critical for limiting the spread of LCMV to other organs and to prevent exhaustion of CD8 T cells (13).…”

CD169 identifies an activated CD8+T cell subset in regional lymph nodes that predicts favorable prognosis in colorectal cancer patients

“…Studies in murine systems have shown that CD169 C Mf contribute to antigen retention and cross-presentation of antigens to CD8 C T cells in the LN, thereby functioning as powerful APCs that significantly contribute to CTL responses. 21,23,26 The mechanism of generating CD169 C CD8 C T cells is presently unknown. T lymphocytes located adjacent to CD169 C Mf have been shown to be stained for CD169 due to blebs from CD169 C Mf undergoing fragmentation.…”

“…[21][22][23][24][25] A recent study demonstrated that CD169 C Mf could effectively generate CTL responses by cross-priming CD8 C T cells, which in turn, conferred immunity against re-exposure to the malignant cells. 26 The expression of CD169 in tumor-draining LN and its association with survival in CRC patients has been recently reported 27 ; however, the specific composition and function of CD169 C cells in tumor-draining LNs of cancer patients remain largely unknown. In the current study, we addressed this issue in CRC and identified a novel T cell subset, CD169 C CD8 C T cells.…”