Sending Mixed Signals in Sepsis
Staphylococcus aureus is a normal denizen of the human microbiota colonizing skin and nasopharyngeal regions under steady state conditions but has the potential to trigger sepsis upon events inciting immune dysregulation. Both innate and adaptive immunity contribute to systemic inflammation during sepsis; however, it is not yet known how systemic immune responses to S. aureus enterotoxins are instigated. In this issue, Svedova et al. (p. 4510) investigated the immediate adaptive and innate immune responses to S. aureus enterotoxin A (SEA) inhalation in mice. They found that this treatment in mice induced blood leukocytosis, one of the hallmarks of human sepsis, with increased counts for blood-derived neutrophils and monocytes observed at 4 h post-SEA inhalation. The draining lymph nodes (LNs) of SEA-treated mice accumulated CD11b+Ly6B.2+ inflammatory cell populations in the T cell zones, rather than in the subcapsular sinus area as was found in a previous study, in a T cell–dependent manner. These mice also harbored dendritic cells (DCs) and SEA-specific T cells expressing mRNAs for chemokines integral to monocyte and neutrophil recruitment, including Cxcl1, 2 (DCs) and Cxcl3, 4 (T cells). To help determine the signaling pathways by which T cells recruited inflammatory cell populations to the blood and LNs, the authors performed gene expression analyses on SEA-specific T cells and found upregulation of both Tnf and costimulatory molecule gene expression, including those encoding CD40L and 4-1BBL. Treating mice with Abs to block CD40L and 4-1BBL before SEA challenge did not impede monocyte or neutrophil migration into the blood or LNs. However, neutralizing Abs specific for either the costimulatory molecule CD28 or TNF revealed nonredundant roles for TNF in the recruitment of neutrophils into the blood and for CD28 in the chemotaxis of monocytes into the blood and lymph tissue. Both pathways had overlapping roles in the recruitment of neutrophils into the lymph tissue. Together, these data suggest that TNF and CD28 signaling pathways are important players in the SEA-induced T cell–dependent recruitment of inflammatory monocytes and neutrophils into lymph nodes and that pharmaceutical modulation of these pathways may be clinically relevant in the control of sepsis.
Handing Off Ag To Boost Vaccination
Effector CD8+ T cells are rapidly generated following booster immunizations, and these cells may hamper the immune response by killing APCs, thereby curtailing central memory T cell (TCM) responses. Previous work had shown that postboost vaccination with recombinant rhabdoviruses could lead to rapid secondary T cell expansion, and Bridle et al. (p. 4587) dissected the requirements for this expansion. Immunization of mice by i.v. inoculation with a recombinant human adenovirus (Ad) vector expressing an OVA-derived CD8+ T cell epitope coupled to luciferase (Ad-SIINFEKL [SIIN]) resulted in expansion of OVA-specific effector T cells (TEFF), and boosting with a vesicular stomatitis virus (VSV) vector expressing the same Ag (VSV-SIIN) resulted in OVA-specific T cells dominating the circulating pool. Other routes of vaccination were not as effective at boosting the CD8+ T cell response, and similar results were achieved even with a less immunogenic Ag. Boosted mice had the earliest evidence of Ag-specific T cell proliferation in the spleen, and splenectomized mice had diminished secondary proliferation, demonstrating the importance of the spleen for this expansion. To identify which T cell subset was proliferating during the secondary expansion, OVA257–264-specific CD8+ T cells were sorted into TEFF, TCM, and T effector memory subsets before adoptive transfer into congenic hosts. Strikingly, TCM expanded over 100-fold 5 d following VSV-SIIN vaccination, whereas TEFF contracted. Secondary expansion of CD8+ T cells was abrogated in B cell-deficient mice, although MHC class I expression by the B cells was dispensable, indicating that the B cells were not directly serving as APCs. Mice depleted of CD11c+ cells also could not support the robust secondary expansion of CD8+ T cells, and coculture experiments demonstrated that B cells transferred Ag to dendritic cells (DCs), which then presented Ag to T cells. These findings indicate that despite TEFF cell activation, this method of prime-boost vaccination can generate robust CD8+ T cell expansion in the spleen by B cells passing Ag to DCs.
C3aR Contributes to Cancer
Products of the complement cascade, such as C5a, have been shown to promote tumor growth. In this issue, Nabizadeh et al. (p. 4783) examined how a mouse model of melanoma was affected by the complement receptor C3aR, which is expressed on myeloid cells and stromal cells. B16-F10 melanoma growth was slowed and survival improved in C3aR-deficient (C3aR−/−) relative to wild-type (WT) mice. Plasma G-CSF was lower in C3aR−/− mice, and some TLR and chemokine pathway genes were upregulated in the tumors. C3aR host expression did not affect total number of tumor-infiltrating CD45+ leukocytes, but the tumors in C3aR−/− mice contained fewer macrophages, more neutrophils, and more effector CD4+ T cells than in the tumors of WT mice, with similar patterns observed in the spleen and draining lymph nodes. Daily injection of a C3aR antagonist 7 d after tumor inoculation in WT mice led to similar results as in C3aR−/− mice with regard to melanoma growth and neutrophil and CD4+ T cell recruitment. Compared with administration of an isotype control, Ab depletion of neutrophils in C3aR−/− mice led to increased tumor growth and relatively fewer CD4+ T cells in the tumor. To enhance the significance of their findings, the authors then tested a second melanoma model, a colon cancer model, and a mammary carcinoma model in C3aR−/− mice. All three types of tumors grew more slowly and excised tumor weights were less than in WT mice. Collectively, these data indicate that C3aR promotes tumor growth, and may be a valuable target for immunotherapy in multiple cancer types.
Illuminating IL-15 Regulation in Lymphodepletion
Interleukin-15, present on the cell surface and as soluble IL-15/IL-15Rα complexes (sIL-15 complexes), is known to regulate lymphopenia-induced T cell proliferation. This proliferation was initially thought to be due to a cytokine sink effect, but sIL-15 complexes have been shown to be upregulated in various models of lymphopenia through mechanisms that are as yet undefined. Anthony et al. (p. 4544) examined IL-15 regulation in RAG-deficient (RAG−/−) mice and in two lymphopenia models involving substantial cell death, total body irradiation (TBI) and Thy1 Ab–mediated T cell depletion. Levels of sIL-15 complexes in RAG−/− mice were equivalent to levels in wild-type (WT) mice, suggesting that IL-15 is not upregulated universally in all models of lymphopenia. TBI led to an increase of cell-surface IL-15 expression by myeloid cells but not dendritic cells (DCs), and analysis of different knockout mice demonstrated that TBI-induced sIL-15 complex expression was derived from CD11c+ and LysM+ cells. T cell depletion with an anti–Thy1 Ab increased serum levels of sIL-15 complexes and cell-surface IL-15 on CD8+ DCs, monocytes, and macrophages; these effects were partially dependent on type I IFN signaling. Recognition of cytoplasmic DNA by stimulator of IFN genes (STING) leads to type I IFN expression, and administration of a STING agonist induced sIL-15 complexes in a type I IFN-dependent manner. In contrast, Tmem173-deficient mice, which lack an intact STING pathway, partially upregulated sIL-15 complexes following TBI or Thy1 Ab depletion, suggesting that these models of lymphopenia may involve STING-independent pathways that induce type I IFN. Using serial adoptive transfers, memory CD8+ T cell proliferation was shown to be enhanced by IL-15 following Ab depletion of host cells. These results shed light on the complex inflammatory signals that prompt T cell proliferation in response to lymphopenia induced by various means.
B Cells Say IDO to Arthritis
The nonredundant immunoregulatory enzymes indoleamine 2,3-dioxygenases IDO1 and IDO2 have been linked to immune tolerance, but many studies have been conducted with pharmacological inhibitors that block both enzymes, necessitating use of genetic knockouts to isolate which enzyme is responsible for the observed phenotypes. Examination of IDO2-knockout (ko) mice identified a role for this enzyme, which is expressed in certain tissues and APCs, in the KRN model of arthritis. In this issue Merlo et al. (p. 4487) explored the mechanisms by which IDO2 attenuates inflammatory adaptive responses. Arthritis was induced by adoptively transferring KRN T cells specific for the autoantigen glucose-6-phosphate isomerase and B cells into Rag-deficient hosts expressing the I-Ag7 molecule capable of presenting the autoantigen. When IDO2 ko B cells were cotransferred with KRN T cells, the hosts did not develop arthritis; however, arthritis was induced when IDO2 ko KRN T cells were transferred with wild-type (wt) B cells. These results indicated that B cell IDO2 expression was both necessary and sufficient for arthritis development, and further experiments demonstrated a need for Ag presentation by B cells. Transfer of B220+CD11c+ age-associated B cells did not cause arthritis, whereas transfer of purified marginal zone B cells initiated a more robust arthritic response than purified follicular B cells. Adoptive transfer experiments also showed that, unlike wt B cells, IDO2 ko B cells were unable to initiate contact hypersensitivity, confirming the results in a second model. CD40 levels were reduced on IDO2 ko B cells following BCR stimulation, indicating that the lack of IDO2 may impair T–B cell collaboration. These results identify IDO2 as an important immunoregulatory enzyme involved in B cell Ag presentation to T cells in inflammatory immune responses.
- Copyright © 2016 by The American Association of Immunologists, Inc.
