In This Issue

doi:10.4049/jimmunol.1690013

Suppressing Skin Sensitivity

Contact hypersensitivity (CHS), which models allergic contact dermatitis, is mediated by hapten-specific CD8⁺ T cells and neutrophils and can be controlled by regulatory T cells (Tregs). Complexes consisting of IL-2 and the anti–IL-2 Ab JES6-1 can expand Tregs and suppress inflammatory diseases, leading El Beidaq et al. (p. 1567) to assess whether in vivo expansion of Tregs using IL-2/JES6-1 could effectively treat CHS. Administration of IL-2/JES6-1 to mice either before sensitization or during priming but before challenge caused the expansion of both thymically generated natural Tregs (nTregs) and peripheral Tregs (pTregs) and suppressed CHS, as measured by a reduction in ear swelling relative to control animals. In addition to expanding Tregs, IL-2/JES6-1 treatment reduced the infiltration of neutrophils and CD8⁺ T cells into ear tissue and downregulated CD86 expression on dendritic cells (DCs) without affecting DC migration. Restoration of CHS despite IL-2/JES6-1 treatment in mice in which Tregs were selectively depleted confirmed that Tregs expanded by IL-2/JES6-1 were responsible for CHS suppression. In Treg-sufficient mice, suppression of CHS using IL-2/JES6-1 was maintained for at least 22 d following treatment and was specific to the sensitizing allergen but not limited to the site of the initial challenge. This long-lasting protection was accompanied by a protracted reduction in hapten-specific CD8⁺ T cells and long-lived expansion of both nTregs and pTregs in the lymph nodes. These data indicate that IL-2/JES6-1 treatment can expand Tregs that suppress CHS during both the priming and effector phase of disease and maintain this suppression long term.

With IL-2, Timing Is Everything

Augmenting CD8⁺ T cell responses, including establishing durable memory, is an ongoing goal of vaccinations against infections and tumors. In this issue, Kim et al. (p. 1754) investigated whether enhancement of IL-2 signals using IL-2/anti–IL-2 Ab complexes (IL-2c) during responses to dendritic cell (DC)-based vaccination could effectively augment the induction of protective memory CD8⁺ T cells. Relative to treatment with rat Ig, treatment of mice with IL-2c on days 4–6 after immunization with Ag-pulsed DCs greatly increased the population of terminally differentiated Ag-specific CD8⁺ effector T cells which, in time, contracted via Bim-mediated apoptosis. However, this relatively late treatment did not affect memory CD8⁺ T cell numbers, suggesting that differentiation of effector and memory T cells were separable processes in this system. In contrast, IL-2c treatment during days 1–3 after DC immunization (when priming is taking place) resulted in expansion of both effector and memory CD8⁺ T cells. Analysis of the expanded Ag-specific T cells showed that early, but not late, IL-2c treatment resulted in a metabolic profile favoring memory precursor effector cells rather than short-lived effector cells. Suggesting an indirect effect of IL-2c on T cells via modulation of DC function, the authors observed downregulation of CD80/86 on DCs following early IL-2c treatment in vivo. This downregulation was mediated by regulatory T cells (Tregs) expanded by early IL-2c treatment acting through a mechanism involving CTLA-4. Blockade of CTLA-4 in vivo impaired the generation of CD8⁺ memory T cells but did not impact effector T cell generation, suggesting that IL-2c causes expansion of memory precursor effector cells by inducing expansion of CTLA-4-expressing Tregs that interact with DCs and cause them to favor the promotion of memory CD8⁺ T cell development. These results are broadly applicable to vaccine design and support the potential for therapeutic modulation of T cell immunity through manipulation of IL-2 signals.

Ectosomes Irk NKs

Transfusion of platelets is a potentially lifesaving therapy that, unfortunately, is accompanied by an increased risk of infection due to the immunosuppressive properties of platelets. Platelets are hypothesized to modulate the immune system through the activity of ectosomes, which are cell surface-derived vesicles that are released into the periphery, often carrying soluble mediators such as cytokines. Although previous work has demonstrated that platelet-derived ectosomes (PLT-Ecto) have the ability to alter the activity of macrophages and dendritic cells, little is known about the interactions between NK cells and ectosomes. In this issue, Sadallah et al. (p. 1663) investigated the potential immunosuppressive effects of PLT-Ecto on human NK cells. Overnight incubation of healthy NK cells with PLT-Ecto resulted in significant suppression of NK cell activation and function, as evidenced by downregulation of activating surface receptors NKG2D, NKp30, and DNAM-1, and a decrease in surface CD107a and intracellular IFN-γ. This phenotype was rescued by the neutralization of TGF-β1, a cytokine ectosomes have previously been demonstrated to carry, suggesting that the PLT-Ecto suppression of NK cell activity and function was mediated by TGF-β1. Exposure of NK cells to PLT-Ecto decreased surface expression of the important stimulatory signaling adaptor molecule DAP12 in a manner similar to incubation with TGF-β1, suggesting that suppression of the DAP12 pathway mediates NK cell suppression by PLT-Ecto–derived TGF-β1. While it remains unknown whether PLT-Ecto suppression of NK cells takes place in vivo, this study highlights the importance of studying NK cell function in patients receiving large amounts of platelets, such as recipients of allogenic stem cell transplants, in which posttransplant NK cell function is especially advantageous.

Generating GCs with YY1

In germinal centers (GCs), the important process of Ab affinity maturation takes place; however, rapid GC B cell proliferation combined with the error-prone DNA repair occurring during somatic hypermutation and class switch recombination can result in the development of B cell lymphomas. To better understand the regulation of the GC reaction, Trabucco et al. (p. 1699) analyzed the role in GCs of the transcription factor YY1, which can either activate or repress target genes. Binding sites for YY1 have been observed in the promoters of GC-specific genes, and the authors found that levels of YY1 were increased in B cells inside relative to outside the GC. Compared with control animals, mice in which YY1 was specifically deleted in GC B cells (YY1^CKO mice) had both significantly reduced numbers of GC B cells following immunization and a selective decrease in cells in the dark zone of the GC. Some GC B cells were still generated in the YY1^CKO mice, but the numbers of these cells decreased between days 6 and 10 following immunization, suggesting that the GC reaction could be initiated, but that defects in GC B cell proliferation and/or survival were responsible for the overall impairment in GCs. No deficiencies in proliferation were observed in GC B cells of YY1^CKO mice, but apoptosis was specifically increased in these cells. Thus, the YY1 transcription factor is important for effective GC reactions by regulating the survival of GC B cells and may also have an oncogenic role in the development of B cell lymphomas, as YY1 expression is upregulated in lymphomas and correlates with poor prognosis of lymphoma patients.

Gut Microbes Modulate Splenic T Cells in Sepsis

The high mortality rate of sepsis has previously been ascribed in part to acute lymphopenia followed by a prolonged period of immune paralysis that decreases the ability of the host to respond to secondary infections. Previous work demonstrated that recovery of CD4⁺ T cells following cecal ligation and puncture (CLP)-induced sepsis in mice occurred primarily by Ag- and thymus-independent homeostatic proliferation. In this issue, Cabrera-Perez et al. (p. 1692) investigated the effect of intestinal microbiota on the recovery of the CD4⁺ T cell population following a septic event by assessing if a population of CD4⁺ T cells could respond directly to gut microbiome–derived Ag. Two days following CLP-induced sepsis, mice that were not colonized with segmented filamentous bacteria (SFB⁻) had a decrease in the number of SFB-specific splenic CD4⁺ T cells while SFB-specific CD4⁺ T cells in colonized mice (SFB⁺) demonstrated increases in number and surface expression of CD44, suggesting activation of endogenous SFB-specific CD4⁺ T cells. To determine if sepsis can influence SFB-specific CD4⁺ T cell function, SFB⁺ and SFB⁻ mice were challenged with attenuated Listeria monocytogenes expressing SFB Ag (att. Lm-SFB) 30 d after CLP treatment. SFB-specific CD4⁺ T cells in SFB⁺ mice showed significant increases in number and intracellular IFN-γ following att. Lm-SFB infection, whereas SFB-specific CD4⁺ T cells in SFB^- mice decreased in number and demonstrated no significant change in intracellular IFN-γ. When challenged with a virulent Listeria strain expressing SFB Ag 30 d after CLP, SFB⁺ mice had reduced bacterial loads that correlated with increased survival while SFB^- mice had increased bacterial loads and decreased survival. Taken together, these data suggest that SFB Ag exposure during sepsis primes SFB-specific CD4⁺ T cells to mediate enhanced protection following a second Ag encounter. This study demonstrates that resident gut microbes may play a role in shaping the quantity and quality of CD4⁺ T cell populations in the spleen during sepsis recovery, and these observations suggest a link between gut microbiome composition, intestinal barrier health, and susceptibility to secondary infection following a septic event.