Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Abstract

DCs represent the major cell type leading to polarized T-helper (Th) cell responses in vivo. Here, we asked whether the instruction of murine Th2 responses by DCs matured with the proinflammatory cytokine TNF is qualitatively different from maturation by different types of TLR4/MyD88-dependent variant-specific surface glycoproteins (VSGs) of Trypanosoma brucei (T. brucei). The results obtained by analyzing DC surface markers, Notch ligand mRNA, cytokines, asthma, and experimental autoimmune encephalomyelitis (EAE) models as well as performing microarrays indicate that both types of stimuli induce similar inflammatory, semi-mature DC profiles. DCs matured by TNF or VSG treatment expressed a common inflammatory signature of 24 genes correlating with their Th2-polarization capacity. However, the same 24 genes and 4498 additional genes were expressed by DCs treated with LPS that went on to induce Th1 cells. These findings support the concept of a default pathway for Th2-cell induction in DCs matured under suboptimal or inflammatory conditions, independent of the surface receptors and signaling pathways involved. Our data also indicate that quantitative differences in DC maturation might direct Th2-vs Th1-cell responses, since suboptimally matured inflammatory DCs induce default Th2-cell maturation, whereas fully mature DCs induce Th1-cell maturation.Key words: DCs . microarray . Th2 cells . TNF . Trypanosoma Supporting Information available online IntroductionDCs play a fundamental role in the induction of adaptive immune responses as well as in the maintenance of peripheral tolerance [1][2][3]. Through the expression of pattern-recognition receptors (PPRs) such as Toll-like receptors (TLRs), DCs are able to sense a wide array of pathogens and mount an appropriate T-helper (Th) cell response [4]. Naïve CD4 1 T-cell precursors can differentiate into a variety of Th-cell lineages characterized by the cytokines produced: Th1 cells secrete predominately IFN-g, Th2 cells release IL-4, IL-5, and IL-13 and Th17 cells typically produce . Although the contribution of DCs for CD4 1 Th-cell polarization is under debate [6], several DC-derived mechanisms have been described to significantly direct Th-cell phenotypes. 3479DCs change their maturation status by upregulating surface expression of MHC class II and costimulatory molecules and by producing a defined set of cytokines to optimally induce distinct Th-cell responses [7][8][9]. Due to their immunostimulatory function, DCs are of particular interest in immunotherapy settings, such as cancer therapy and infectious disease intervention [10,11]. Thus, the Th-cell polarizing profile defined by the maturation signature of DCs is of vital interest. Several membrane markers on DCs and soluble factors secreted by DCs have been described to polarize toward Th2 responses. These include costimulatory molecules such as OX40 [12], , the Notch family member Jagged-2 [14], the cytokine IL-6 [15], or arachidonic acid metabolites such as PGE 2 [16][17][18]. Much less is known about the fac...

The Trypanosoma brucei gambiense Secretome Impairs Lipopolysaccharide-Induced Maturation, Cytokine Production, and Allostimulatory Capacity of Dendritic Cells

“…For instance, a default Th2-cell differentiation pathway independent of the surface receptors and signaling pathways involved was demonstrated to be induced by DCs matured under suboptimal inflammatory conditions. The data also indicated that quantitative differences in DC maturation might direct Th2-versus Th1-cell responses, since suboptimally matured inflammatory DCs induce Th2-cell maturation by default, whereas fully mature DCs induce Th1-cell maturation (18). Similar changes in surface markers and cytokine profiles have also been reported for Trypanosoma cruzi and Leishmania, which, in addition to African trypanosomes, present intracellular stages in the infected host.…”

“…In a trypanosome infection, DCs play a crucial role in the activation of Th-cell responses, with DCs being the primary cell population inducing a VSG-specific response in naive T cells (15). However, VSG induces partial maturation of DCs, leading to a Th2-cell response that does not exert antitrypanosome activity (18). Recently, natural killer T cells and regulatory T cells have been demonstrated to influence the outcome of a trypanosome infection (41)(42)(43).…”

“…Interestingly, resistance to trypanosome infection was associated with upregulation of costimulatory molecules, secretion of interleukin-12 (IL-12), and presentation of VSG peptides to T cells in vivo (15). However, tumor necrosis factor alpha (TNF-␣)-and nitric oxide (NO) synthase 2-producing DCs are responsible for trypanosome infection-associated pathogenesis (17), but the regulation of DC populations appears to be even more complex, since T. brucei VSG or TNF-␣ was shown to induce partial maturation of DCs, generating a default Th2-cell differentiation response, whereas lipopolysaccharide (LPS)-induced full maturation of the same DCs was shown to generate a Th1-cell response (18).…”

Synchronization of Dendritic Cell Activation and Antigen Exposure Is Required for the Induction of Th1/Th17 Responses

“…A default pathway for Th2 cell induction was recently reported when DCs were matured under suboptimal conditions (42). As the induction of Th1 or Th2 cells is directly influenced by the level of TCR-mediated signaling (43) Given the preserved Th2 responses, the lack of interference of free fluid Ag on B cell responses is readily explained: indeed, Ab responses increase when the tightness of Ag binding to aluminum salts is reduced (53,54).…”

A Cell‐Based Assay Reveals Nuclear Translocation of Intracellular Domains Released by SPPL Proteases

“…Sfrp2 mRNA has been detected in bone marrow-derived dendritic cells (BMDC) by transcriptomic profiling (31). Because dendritic cells abundantly express endogenous CD74, we analyzed consequences of a reduced ICD generation in BMDCs.…”