Differential Pattern Recognition Receptor Expression but Stereotyped Responsiveness in Rat Spleen Dendritic Cell Subsets

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261

The TLRs 7, 8, and 9 stimulate innate immune responses upon recognizing pathogen nucleic acids. U-rich RNA sequences were recently discovered that stimulate human TLR7/8-mediated or murine TLR7-mediated immune effects. In this study we identified single-stranded RNA sequences containing defined sequence motifs that either preferentially activate human TLR8-mediated as opposed to TLR7- or TLR7/8-mediated immune responses. The identified TLR8 RNA motifs signal via TLR8 and fail to induce IFN-α from TLR7-expressing plasmacytoid dendritic cells but induce the secretion of Th1-like and proinflammatory cytokines from TLR8-expressing immune cells such as monocytes or myeloid dendritic cells. In contrast, RNA sequences containing the TLR7/8 motif signal via TLR7 and TLR8 and stimulate cytokine secretion from both TLR7- and TLR8-positive immunocytes. The TLR8-specific RNA sequences are able to trigger cytokine responses from human and bovine but not from mouse, rat, and porcine immune cells, suggesting that these species lack the capability to respond properly to TLR8 RNA ligands. In summary, we describe two classes of single-stranded TLR7/8 and TLR8 RNA agonists with diverse target cell and species specificities and immune response profiles.

Section: Discussionmentioning

confidence: 81%

Identification of RNA Sequence Motifs Stimulating Sequence-Specific TLR8-Dependent Immune Responses

Forsbach¹,

Némorin²,

Montino³

et al. 2008

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261

“…Unlike in human, rat pDC express low levels of TLR4 and exhibit in vitro response to LPS (18). Interestingly, only pDC stimulated with either TLR7 or TLR 9 ligands (loxoribine and CpG2006, respectively) were able to promote strong proliferation of CD4 ϩ CD25 high T cells (Fig.…”

Section: Cd25mentioning

confidence: 89%

“…17 and our unpublished observations). Both subsets of cDC express a large repertoire of TLR but only CD4 Ϫ DC produced high levels of IL-12 (18), whereas pDC selectively express TLR7 and TLR9 and produce large amounts of type I IFN as well as IL-12p40. In the steady-state in vivo, the phenotype of pDC is immature and their role in T cell stimulation remains controversial (19).…”

Section: N Aturally Occurring Cd4mentioning

confidence: 99%

See 1 more Smart Citation

Differential Control of T Regulatory Cell Proliferation and Suppressive Activity by Mature Plasmacytoid versus Conventional Spleen Dendritic Cells

Ouabed

Hubert

Chabannes

et al. 2008

Self Cite

Anergy and suppression are cardinal features of CD4+CD25+Foxp3+ T cells (T regulatory cells (Treg)) which have been shown to be tightly controlled by the maturation state of dendritic cells (DC). However, whether lymphoid organ DC subsets exhibit different capacities to control Treg is unclear. In this study, we have analyzed, in the rat, the role of splenic CD4+ and CD4− conventional DC and plasmacytoid DC (pDC) in allogeneic Treg proliferation and suppression in vitro. As expected, in the absence of exogenous IL-2, Treg did not expand in response to immature DC. Upon TLR-induced maturation, all DC became potent stimulators of CD4+CD25− T cells, whereas only TLR7- or TLR9-matured pDC induced strong proliferation of CD4+CD25+Foxp3+ T cells in the absence of exogenous IL-2. This capacity of pDC to reverse Treg anergy required cell contact and was partially CD86 dependent and IL-2 independent. In suppression assays, Treg strongly suppressed proliferation and IL-2 and IFN-γ production by CD4+CD25− T cells induced by mature CD4+ and CD4− DC. In contrast, upon stimulation by mature pDC, proliferating Treg suppressed IL-2 production by CD25− cells but not their proliferation or IFN-γ production. Taken together, these results suggest that anergy and the suppressive function of Treg are differentially controlled by DC subsets.

“…2A). Recent work has shown that the expression profiles of TLRs differ between DCs and monocyte/ macrophage lineage cells (8). For example, TLR3 and TRL10 are expressed at high levels in DCs.…”

Section: Cd8mentioning

confidence: 99%

Rat CD4+CD8+ Macrophages Kill Tumor Cells through an NKG2D- and Granzyme/Perforin-Dependent Mechanism

Baba

Iwasaki

Maruoka

et al. 2008

We previously identified a subpopulation of monocyte/macrophage lineage cells expressing both CD4 and CD8. This subpopulation was expanded in rat peripheral blood and spleen after immunization with adjuvants containing killed tuberculosis germs. CD4+CD8+ monocytes/macrophages obtained from preimmunized rats exhibited a Th1-type cytokine/chemokine profile, expressed high levels of Fas ligand, perforin, granzyme B, and NKR-P2 (rat ortholog of human NKG2D), and killed certain tumor cells. In the present study, we confirmed that CD4+CD8+ monocytes/macrophages are distinct from splenic dendritic cells (DCs) or IFN-producing killer DCs. In vitro cytotoxic assays revealed that CD4+CD8+ macrophages killed tumor cells in a cell-cell contact-dependent manner and that expression of the retinoic acid early transcript 1 (a ligand for NKG2D) made tumor cells susceptible to killing by CD4+CD8+ macrophages. Furthermore, inhibitors of granzyme and perforin significantly decreased cytotoxic activities of CD4+CD8+ macrophages. Consistent with these in vitro findings, preimmunization with adjuvants containing killed tuberculosis germs elevated the expression of granzyme B in tumor-infiltrating CD4+CD8+ macrophages and significantly inhibited the growth of inoculated tumor cells. Our current work demonstrates that CD4+CD8+ macrophages are a unique subpopulation of monocyte/macrophage lineage cells that kill tumor cells in an NKG2D- and granzyme/perforin-dependent mechanism.