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  1. Top of page
  2. Cover image
  3. Expansion of human Treg cells in vivo: Flt3L takes centre stage
  4. Blimp-1 in HIV-1 pathogenesis: A new player in the game
  5. IL-36 cytokines: New IL-1 family members that balance T-cell responses against Aspergillus
  6. Absence of SHIP…wrecks affinity maturation
  7. IL-27 induces “stemness” of tumor antigen specific CTLs and promotes CTL survival
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Our cover image shows a confocal micrograph of a mouse lung challenged with ovalbumin. The cryosection was stained with DAPI (blue), for smooth muscle actin (red) and shows IL-33 expression (green). The Il33Cit/+ reporter mouse line was generated using GFP-derived citrine fluorescence as a surrogate for IL-33 mRNA expression with the citrine gene directly downstream of the Il33 start codon. The image is taken from Hardman et al., (pp. 488–498) where the authors define the temporal and spatial expression of IL-33 during allergic lung inflammation. The authors further show that type-2 pneumocytes are the major source of IL-33 after exposure to ovalbumin, and demonstrate a possible role for IL-33 early in the induction of nuocytes and type-2 responses. Together, these findings show that Il33Cit/+ mice could be an important tool for dissection of this inflammatory pathway in vivo.

Expansion of human Treg cells in vivo: Flt3L takes centre stage

  1. Top of page
  2. Cover image
  3. Expansion of human Treg cells in vivo: Flt3L takes centre stage
  4. Blimp-1 in HIV-1 pathogenesis: A new player in the game
  5. IL-36 cytokines: New IL-1 family members that balance T-cell responses against Aspergillus
  6. Absence of SHIP…wrecks affinity maturation
  7. IL-27 induces “stemness” of tumor antigen specific CTLs and promotes CTL survival
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FoxP3+ regulatory T (Treg) cells constitute an important component of the immune regulatory network which prevents autoimmunity and restrains overwhelming inflammatory reactions. A better understanding of the mechanisms involved in the homeostasis of human Treg cells could lead to therapeutic applications by modulating the frequency and activity of this cell population. In this issue, Klein et al. demonstrate that, in keeping with previous pre-clinical studies, administration of the hematopoietic growth factor Flt3L leads to an expansion of FoxP3+ Treg cells in human subjects. This is an indirect effect, whereby the Flt3L-expanded pool of CD1c+ myeloid dendritic cells induces proliferation of pre-existing Treg cells. These findings suggest that Flt3L, which already has a well-established clinical safety profile, could be used as a therapeutic agent in the treatment of autoimmune conditions and in the setting of transplantation medicine, by promoting the establishment of Treg-cell-mediated tolerance towards autoantigens and allografts.

Blimp-1 in HIV-1 pathogenesis: A new player in the game

  1. Top of page
  2. Cover image
  3. Expansion of human Treg cells in vivo: Flt3L takes centre stage
  4. Blimp-1 in HIV-1 pathogenesis: A new player in the game
  5. IL-36 cytokines: New IL-1 family members that balance T-cell responses against Aspergillus
  6. Absence of SHIP…wrecks affinity maturation
  7. IL-27 induces “stemness” of tumor antigen specific CTLs and promotes CTL survival
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The fine control of T-cell differentiation and its impact on HIV disease progression is poorly understood. In this issue, Seddiki et al. demonstrate that B-lymphocyte-induced maturation protein-1 (Blimp-1/Prdm1) is highly expressed in CD4+ T cells from chronically HIV-infected (CHI) patients with progressive disease compared with Long Term non-Progressors (LTNPs) or healthy controls. Blimp-1 expression increased significantly when CD4+ T cells were stimulated through the T-cell receptor in the presence of IL-2 and this increase appears to be translationally regulated by microRNA-9 (miR-9). Furthermore, the authors show that overexpression of miR-9 induces Blimp-1 repression, restoring IL-2 secretion in CD4+ T cells via reduction in the binding of Blimp-1 to the il-2 promoter. In CHI patients, who have reduced IL-2 expression and T-cell dysfunction, a differential expression of both miR-9 and Blimp-1 in CD4+ cells compared with those from LTNPs was shown. These findings identify a novel miR-9/Blimp-1/IL-2 axis that is dysregulated in progressive HIV infection.

IL-36 cytokines: New IL-1 family members that balance T-cell responses against Aspergillus

  1. Top of page
  2. Cover image
  3. Expansion of human Treg cells in vivo: Flt3L takes centre stage
  4. Blimp-1 in HIV-1 pathogenesis: A new player in the game
  5. IL-36 cytokines: New IL-1 family members that balance T-cell responses against Aspergillus
  6. Absence of SHIP…wrecks affinity maturation
  7. IL-27 induces “stemness” of tumor antigen specific CTLs and promotes CTL survival
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Interleukin-1 family cytokines are key players in the induction of T-helper cell responses. Recently, new IL-1 family members, the IL-36 cytokines, were discovered. These cytokines were found to play a prominent role in inflammatory skin diseases such as psoriasis. In this issue, Gresnigt et al. show that the addition of exogenous IL-36 receptor antagonist (IL-36Ra) to peripheral blood mononuclear cell (PBMC) cultures suppresses Aspergillus-induced Th17 and Th1 type responses, but does not modulate innate, Th2- and regulatory T-cell responses. The authors further demonstrate that inhibition of endogenous IL-36Ra induced by Aspergillus itself results in increased Th17 and Th1 responses by PBMCs, providing evidence that the IL-36 receptor pathway is actively involved in regulating Aspergillus-induced T-cell responses.

Absence of SHIP…wrecks affinity maturation

  1. Top of page
  2. Cover image
  3. Expansion of human Treg cells in vivo: Flt3L takes centre stage
  4. Blimp-1 in HIV-1 pathogenesis: A new player in the game
  5. IL-36 cytokines: New IL-1 family members that balance T-cell responses against Aspergillus
  6. Absence of SHIP…wrecks affinity maturation
  7. IL-27 induces “stemness” of tumor antigen specific CTLs and promotes CTL survival
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The development of high affinity antibodies against pathogens is a cornerstone of immune defense. The tightly regulated process of affinity maturation ensures that B cells with high affinity receptors are preferentially selected through the germinal center reaction. In this issue, Leung et al. demonstrate the importance of the signaling molecule SH2-domain-containing inositol 5′-phosphatase (SHIP) in modulating B-cell activation thresholds during B-cell affinity maturation in the germinal center. Using mice with a B-cell-specific SHIP depletion, the authors show that SHIP-deficient B cells are hyperresponsive to in vitro antigen receptor or cytokine stimulation, but produce poor antibody responses in immunization and infection models. SHIP-deficient germinal center B cells undergo somatic hypermutation but maintain low affinity specificities and an increased frequency of nonfunctional B-cell receptors. These results suggest that inhibitory control of B-cell activation is required during affinity-based B-cell selection to avoid survival of deleterious and unproductive rearrangements arising after somatic hypermutation.

IL-27 induces “stemness” of tumor antigen specific CTLs and promotes CTL survival

  1. Top of page
  2. Cover image
  3. Expansion of human Treg cells in vivo: Flt3L takes centre stage
  4. Blimp-1 in HIV-1 pathogenesis: A new player in the game
  5. IL-36 cytokines: New IL-1 family members that balance T-cell responses against Aspergillus
  6. Absence of SHIP…wrecks affinity maturation
  7. IL-27 induces “stemness” of tumor antigen specific CTLs and promotes CTL survival
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IL-27 has been shown to have potent anti-tumor effects involving the induction of anti-tumor cytotoxic T lymphocyte (CTL) responses. However, it remains unclear how IL-27 stimulates CTL responses. In this issue, Liu et al. report that IL-27 exerts three STAT3 activation-mediated effects on tumor antigen-specific CD8+ T cells, using cells from P1CTL mice, whose CD8+ T cells bear a TCR transgene specific for tumor rejection antigen P1A. First, IL-27 upregulates anti-apoptotic molecule Bcl-2 and inhibits activation of Caspase 3 in activated CTLs, which leads to improved survival of these cells. Second, IL-27 induces a unique stem cell/memory precursor cell (MPC) phenotype in activated CTLs, characterized by the upregulation of SOCS3, Bcl-6 and Sca-1. The authors also show that the IL-27 induced “stemness” of CTLs does not significantly affect their cytotoxicity. Third, IL-27 induces high amounts of IL-10 production by CTLs. IL-27-induced CTL IL-10 production therefore contributes to MPC phenotype, T-cell memory and tumor rejection.