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  1. Top of page
  2. Cover image
  3. αβ and γδ cells compete to play in the NKT cell team
  4. The local mucosal microenvironment controls DC immune responses
  5. Double negative Treg cells delete T and NK cells and promote bone marrow chimerism
  6. Complementarities of the regulators: B cells and natural Treg cells join forces to suppress autoimmunity
  7. Unleashing the flames: GILZ downregulation as a promoter of macrophage activation
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The cover is a composite of immunohistochemistry images showing the localization of IL-1Ra (orange in the cover, brown in the original figure) in the liver of WT, IL-1Ra-deficient and hepatocyte-specific IL-1Ra-deficient mice following the induction of concanavalin A (ConA)-induced hepatitis or NaCl-treated controls. The images are taken from Lamacchia et al. (pp. 1294–1303) in which the authors show that hepatocytes produce large amounts of IL-1Ra during the induced liver injury (ConA-induced hepatitis) and, importantly, that this hepatocyte-produced IL-1Ra is required for the resolution of the hepatitis.

αβ and γδ cells compete to play in the NKT cell team

  1. Top of page
  2. Cover image
  3. αβ and γδ cells compete to play in the NKT cell team
  4. The local mucosal microenvironment controls DC immune responses
  5. Double negative Treg cells delete T and NK cells and promote bone marrow chimerism
  6. Complementarities of the regulators: B cells and natural Treg cells join forces to suppress autoimmunity
  7. Unleashing the flames: GILZ downregulation as a promoter of macrophage activation
normal image

By rapidly secreting large amounts of different effector cytokines, NKT cells modulate immune responses and regulate the development of other innate cells. The largest and best studied NKT-cell population is oligoclonal and recognizes glycolipids presented by the nonclassical MHC class I molecule CD1 d on cortical thymocytes, thus triggering the NKT-cell differentiation pathway. The developmental stages associated with this pathway display defined phenotypic and functional characteristics. In this issue, Pereira and Boucontet determine two subpopulations of αβ NKT cells defined by (i) the expression of high levels of PLZF and high IL-4 secretion and (ii) by expression of the NK1.1 marker and high IFN-γ secretion. These are reminiscent of the NK1.1 and NK1.1+ developmental stages respectively. Interestingly, Pereira and Boucontet also show that identical phenotypic and functional stages are present in a population of innate γδ T cells expressing a Vγ1/Vδ6.3 TCR. Furthermore, Pereira and Boucontet observe an increase in NK1.1+ NKT γδ cell numbers in mice Tg for a rearranged Vg1 chain that results in a similar decrease in NK1.1+ NKT αβ cells, thus indicating that both populations compete for a thymic niche.

The local mucosal microenvironment controls DC immune responses

  1. Top of page
  2. Cover image
  3. αβ and γδ cells compete to play in the NKT cell team
  4. The local mucosal microenvironment controls DC immune responses
  5. Double negative Treg cells delete T and NK cells and promote bone marrow chimerism
  6. Complementarities of the regulators: B cells and natural Treg cells join forces to suppress autoimmunity
  7. Unleashing the flames: GILZ downregulation as a promoter of macrophage activation
normal image

DCs deliver antigens to the immune system and determine not only the nature of an immune response but also its location. In the non-inflamed human colon, the local microenvironment contains tissue specific and “tolerogenic” signals. In this issue, Bernardo et al. show that DCs exposed to this microenvironment not only have decreased stimulatory capacity, in comparison with DCs exposed to an inflammatory gut condition, but also imprint responding T cells with a gut-homing profile; these gut-specific T cells may maintain immune tolerance of commensal bacteria and food. In addition, the authors show that there is a pro-inflammatory cytokine profile (mainly mediated by IL-6) and decreased expression of “tolerogenic” signals in the inflamed colonic areas of ulcerative colitis patients. Furthermore, DCs exposed to this microenvironment are shown to have acquired a pro-inflammatory phenotype and to have increased stimulatory capacity. A novel, IL-6-dependent feature of DCs exposed to this inflammatory environment is shown to imprint responding T cells with a skin-homing profile. Together, these findings help the mechanisms of dysregulated immune responses and the development of extra-intestinal manifestations in ulcerative colitis patients to be understood.

Double negative Treg cells delete T and NK cells and promote bone marrow chimerism

  1. Top of page
  2. Cover image
  3. αβ and γδ cells compete to play in the NKT cell team
  4. The local mucosal microenvironment controls DC immune responses
  5. Double negative Treg cells delete T and NK cells and promote bone marrow chimerism
  6. Complementarities of the regulators: B cells and natural Treg cells join forces to suppress autoimmunity
  7. Unleashing the flames: GILZ downregulation as a promoter of macrophage activation
normal image

Donor-specific tolerance by bone marrow (BM) mixed chimerism represents the ideal solution for graft rejection in transplantation. However, this is hindered by T cell- and NK cell-mediated allogeneic BM transplant rejection and graft-versus-host (GVH) disease. In this issue, Su et al. demonstrate that adoptive transfer of double negative (DN) Treg cells prior to allogeneic BM transplantation, in combination with immunosuppression cyclophosphamide, established a stable mixed chimerism that led to specific tolerance to the BM-donor skin allografts. Importantly, DN Treg-cell treated mice did not develop GVH disease. Moreover, numbers of alloreactive CD4+, CD8+ T cells and NK cells were reduced in DN Treg cell-treated mice through a perforin-dependent pathway. Hence, adoptive transfer of DN Treg cells can control both adaptive and innate immune responses, and promote stable mixed chimerism and donor-specific tolerance of BM transplantation under irradiation-free conditions for.

Complementarities of the regulators: B cells and natural Treg cells join forces to suppress autoimmunity

  1. Top of page
  2. Cover image
  3. αβ and γδ cells compete to play in the NKT cell team
  4. The local mucosal microenvironment controls DC immune responses
  5. Double negative Treg cells delete T and NK cells and promote bone marrow chimerism
  6. Complementarities of the regulators: B cells and natural Treg cells join forces to suppress autoimmunity
  7. Unleashing the flames: GILZ downregulation as a promoter of macrophage activation
normal image

B-cell depletion therapy (BCDT) has emerged as a promising approach for the treatment of autoimmune diseases. However, in addition to their pathogenic activities, B cells also have protective functions, associated primarily with their capacity to stimulate Foxp3+ natural regulatory T (Treg) cells, an important immunosuppressive cell type. Thus, BCDT might result not only in elimination of pathogenic B cells but also in reduced Treg cell-mediated protection. In this issue, Hoehlig et al. address this potential concern, asking whether the activation of Treg cells depends on B cells during autoimmune disease, in this case EAE. The authors show that Treg-cell activation proceeds normally in the complete absence of B cells, indicating that impaired Treg-cell function is an unlikely outcome of BCDT. In contrast, this study suggests that B cells and Treg cells provide two distinct layers of regulation that are both essential for the limitation of autoimmune pathology.

Unleashing the flames: GILZ downregulation as a promoter of macrophage activation

  1. Top of page
  2. Cover image
  3. αβ and γδ cells compete to play in the NKT cell team
  4. The local mucosal microenvironment controls DC immune responses
  5. Double negative Treg cells delete T and NK cells and promote bone marrow chimerism
  6. Complementarities of the regulators: B cells and natural Treg cells join forces to suppress autoimmunity
  7. Unleashing the flames: GILZ downregulation as a promoter of macrophage activation
normal image

The activation of a group of innate immune receptors, i.e. the Toll-like receptors (TLRs), has been shown to contribute to both infectious and sterile inflammatory processes. Alveolar macrophages are key players in inflammatory lung diseases. and, in addition to their increased production of inflammatory mediators, their downregulation of anti-inflammatory regulators can also determine disease progression. GILZ (glucocorticoid-induced leucine zipper, TSC22D3) is an anti-inflammatory, glucocorticoid-inducible protein that has been shown to interact with the inflammatory transcription factor NF-κB and, in this issue, Hoppstädter et al. investigate GILZ expression in activated primary human alveolar macrophages, i.e. following TLR activation. The authors show MyD88-dependent GILZ downregulation upon TLR activation, which is mediated by TTP-induced GILZ mRNA destabilization. Functionally, the authors demonstrate that GILZ downregulation amplifies the inflammatory activation of macrophages. These findings suggest that abrogation of GILZ decay under inflammatory conditions represents an interesting pharmacological target that might present therapeutic opportunities that have fewer side effects than steroids.