T Cell Biasing by Activated Dendritic Cells

139

164

The recently described TL1A/DR3 ligand/receptor pair mediates strong costimulation of Th1 cells. Activation of T and NK cells induces DR3 expression, permitting soluble recombinant TL1A to increase IFN-γ production and proliferation of these cells. Gut T cells and macrophages express TL1A, especially in Crohn’s disease (CD), and there is a strong association between CD and tl1a single nucleotide polymorphisms. Murine studies implicate TL1A in gut inflammation. To determine whether professional T cell-activating cells can express TL1A, fresh blood monocytes and monocyte-derived dendritic cells were stimulated with various activating ligands, including TLR agonists, IFN-γ, and immune complexes. FcγR stimulation strongly induced TL1A mRNA in both cell types, which correlated with the detection of TL1A on the cell surface and in cell culture medium. TLR agonists capable of inducing IL-6 and TNF-α in monocytes and dendritic cells did not induce surface nor soluble TL1A. Furthermore, we demonstrate that TL1A production in monocytes leads to enhancement of T cell responses. The induction of TL1A on APCs via specific pathway stimulation suggests a role for TL1A in Th1 responses to pathogens, and in CD.

Section: Discussionmentioning

confidence: 99%

The T Cell Costimulator TL1A Is Induced by FcγR Signaling in Human Monocytes and Dendritic Cells

Prehn

Thomas

Landers

et al. 2007

139

164

“…Regardless of the mechanisms underlying a JAK/STAT-or ISG15-mediated intracellular event, there is no doubt that DC activation status can greatly influence Ag-specific T cell responses and, therefore, disease outcomes (46). Our in vitro, T cell-priming studies using two New World Leishmania species indicate clearly a correlation between DC activation status and the magnitude of T cell activation, confirming the high potential of L. braziliensisinfected DCs in priming naive CD4 ϩ T cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Leishmania braziliensis Infection Induces Dendritic Cell Activation, ISG15 Transcription, and the Generation of Protective Immune Responses

Vargas-Inchaustegui¹,

Luo²,

Soong

2008

Leishmania (Viannia) braziliensis is the causative agent of cutaneous and mucosal leishmaniasis in South America, and the latter is a severe and disfiguring form of the disease. Our understanding of how L. braziliensis parasites interact with dendritic cells (DCs) is limited, partially due to the difficulty in generating axenic amastigotes. In this study, we successfully generated axenic amastigotes of L. braziliensis and used them to test the hypothesis that L. braziliensis infection efficiently triggers innate responses in DCs and the subsequent adaptive immune responses for parasite clearance. This study has revealed unique immunological features of L. braziliensis infection. Firstly, axenic amastigotes showed higher infectivity and the potential to stimulate C57BL/6 (B6) bone marrow-derived dendritic cells to produce IL-12p40 when compared with their promastigote counterparts. Both parasite-carrying and bystander DCs displayed an activated (CD11chighCD45RB−CD83+CD40+CD80+) phenotype. Secondly, L. braziliensis infection triggered transcription and phosphorylation of STAT molecules and IFN-stimulated gene 15 (ISG15). Finally, the self-healing of the infection in mice was correlated to the expansion of IFN-γ- and IL-17-producing CD4+ cells, suggesting the existence of active mechanisms to regulate local inflammation. Collectively, this study supports the view that innate responses at the DC level determine parasite-specific T cell responses and disease outcomes.

“…Immune complex binding to Fc␥R has been shown to increase IL-10 and decrease IL-12 secretion by DC responding to soluble Ag (53). We have previously reported that CRP increases IL-10 production in mouse macrophage cultures and in vivo (17).…”

Section: Discussionmentioning

confidence: 99%

C-Reactive Protein Enhances Immunity to Streptococcus pneumoniae by Targeting Uptake to FcγR on Dendritic Cells

Thomas-Rudolph

Clos

Snapper

et al. 2007

C-reactive protein (CRP) is an acute phase reactant with roles in innate host defense, clearance of damaged cells, and regulation of the inflammatory response. These activities of CRP depend on ligand recognition, complement activation, and binding to FcγR. CRP binds to phosphocholine in the Streptococcus pneumoniae cell wall and provides innate defense against pneumococcal infection. These studies examine the effect of this early innate defense molecule on the development of Abs and protective immunity to S. pneumoniae. Dendritic cells (DC) initiate and direct the adaptive immune response by integrating innate stimuli with cytokine synthesis and Ag presentation. We hypothesized that CRP would direct uptake of S. pneumoniae to FcγR on DC and enhance Ag presentation. CRP opsonization of the R36a strain of S. pneumoniae increased the uptake of bacteria by DC. DC pulsed with untreated or CRP-opsonized R36a were transferred into recipient mice, and Ab responses were measured. In mice challenged with free R36a, CRP opsonization resulted in higher secondary and memory IgG responses to both phosphocholine and pneumococcal surface protein A. Furthermore, mice immunized with DC that had been pulsed with CRP-opsonized R36a showed increased resistance to intranasal infection with virulent S. pneumoniae. The effects of CRP on Ag uptake, Ab responses, and protection from infection all required FcR γ-chain expression on DC. The results indicate that innate recognition by CRP enhances effective uptake and presentation of bacterial Ags through FcγR on DC and stimulates protective adaptive immunity.