Differential control of Helios+/− Treg development by monocyte subsets through disparate inflammatory cytokines

It remains unknown why the occurrence of eczema herpeticum (EH) caused by an extensive disseminated cutaneous infection with HSV-1 or HSV-2 is associated with the exacerbation of atopic dermatitis lesions after withdrawal of treatment. Although regulatory T cells (Tregs) limit the magnitude of HSV-specific T cell responses in mice, their role in the induction and resolution of EH has not been defined. We initially investigated the frequencies, phenotype, and function of Tregs in the peripheral blood of atopic dermatitis with EH (ADEH) patients at onset and after clinical resolution, atopic dermatitis patients without EH, and healthy controls. Tregs with the skin-homing phenotype and the activated/induced phenotype were expanded at onset and contracted upon resolution. Treg-suppressive capacity was retained in ADEH patients and, the expanded Tregs suppressed IFN-γ production from HSV-1–specific CD8+ and CD4+ T cells. The increased frequency of CD14dimCD16+ proinflammatory monocytes (pMOs) was also observed in the blood and EH skin lesions. Thus, pMOs detected in ADEH patients at onset were characterized by an increased ability to produce IL-10 and a decreased ability to produce proinflammatory cytokines, unlike their normal counterparts. Our coculture study using Tregs and pMOs showed that the pMOs can promote the expansion of inducible Tregs. Tregs were detected frequently in the vicinity of HSV-expressing and varicella zoster virus–expressing CD16+ monocytes in the EH lesions. Expansions of functional Tregs, together with pMOs, initially required for ameliorating excessive inflammation occurring after withdrawal of topical corticosteroids could, in turn, contribute to the initiation and progression of HSV reactivation, resulting in the onset of EH.

Section: Hsv-specific Cd4contrasting

confidence: 99%

Pathological Role of Regulatory T Cells in the Initiation and Maintenance of Eczema Herpeticum Lesions

Takahashi

Sato

Kurata

et al. 2014

“…Both LPS and HMGB1 “mature” DC into potent immunostimulatory cells that provide the ample MHC, costimulatory molecules, and IL-1β, −6, −23, and IL-12p70 needed for Th1 and Th17 polarization 52 . Likewise, it has been recently established that IL-12p70 potently inhibits Treg proliferation 53 . Thus, IL-33 is an unconventional alarmin that fails to induce classical DC maturation or support Th1 immunity.…”

Section: Discussionmentioning

confidence: 99%

IL-33 Is an Unconventional Alarmin That Stimulates IL-2 Secretion by Dendritic Cells To Selectively Expand IL-33R/ST2+ Regulatory T Cells

Matta

Lott

Mathews

et al. 2014

191

198

Interleukin (IL)-33 is a recently characterized IL-1 family member that is proposed to function as an alarmin, or endogenous signal of cellular damage, as well act as a pleiotropic cytokine. The ability of IL-33 to potentiate both Th1 and Th2 immunity supports its role in pathogen clearance and disease immunopathology. Yet, IL-33 restrains experimental colitis and transplant rejection by expanding regulatory T cells (Treg) via an undefined mechanism. We sought to determine the influence of IL-33 on hematopoietic cells that drives Treg expansion and underlies the therapeutic benefit of IL-33 administration. Herein, we identify a feedback loop where conventional mouse CD11c+ dendritic cells (DC) stimulated by IL-33 secrete IL-2 to selectively expand IL-33R(ST2+) suppressive CD4+Foxp3+ Treg. Interestingly, this occurs in the absence of classical DC maturation, and DC-derived (innate) IL-2 increases ST2 expression on both DC and interacting Treg. ST2+ Treg represent an activated subset of Foxp3+ cells, demonstrated to be ICOShiCD44hi compared to their ST2− counterparts. Furthermore, while studies have shown that IL-33-exposed DC promote Th2 responses, we reveal that ST2+ DC are required for IL-33-mediated in vitro and in vivo Treg expansion. Thus, we have uncovered a relationship between IL-33 and innate IL-2 that promotes the selective expansion of ST2+ Treg over non-Treg. These findings identify a novel regulatory pathway driven by IL-33 in immune cells that may be harnessed for therapeutic benefit or for robust expansion of Treg in vitro and in vivo.

“…(19) Alternatively, purified CD14 + CD16 − cells and autologous CFSE-labeled CD4+ T cells (2:1 ratio) in the absence or presence of CD16+ monocytes (CD14+CD16 − to CD16+ monocyte ratio of 2:1) were cultured for 7 days with anti-CD3 antibody. In the T cell stimulation experiments that were performed in the absence of monocytes, purified, CFSE stained CD4+ T cells (1.25×10 5 cells/ml) were cultured for 7 days in plates pre-coated with anti-CD3 antibody (clone HIT3α, 1µg/ml).…”

Section: Methodsmentioning

confidence: 99%

“…(13,14) In turn, monocytes can trigger and polarize Th responses (15,16) as well as both stimulate and suppress T-cell responses, depending on monocyte subset and their activation state. (16,17) Indeed, we recently showed in non-SCD setting that CD16+ monocyte subset, which constitute only about 5–10% of total monocytes in healthy individuals, controls Treg/Th proliferation, (18) inhibiting specific Treg subsets (19) while promoting Th1 expansion via IL-12. (18) The role of HO-1 in polarization of T cell responses in human disease setting has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

Hemin Controls T Cell Polarization in Sickle Cell Alloimmunization

Zhong

Bao

Friedman

et al. 2014

Self Cite

Patients with sickle cell disease (SCD) often require transfusions to treat and prevent worsening anemia and other SCD complications. However, transfusions can trigger alloimmunization against transfused red blood cells (RBCs) with serious clinical sequelae. Risk factors for alloimmunization in SCD remain poorly understood. We recently reported altered regulatory T cell (Treg) and T helper (Th) responses with higher circulating Th1 (IFN-γ+) cytokines in chronically transfused SCD patients with alloantibodies as compared to those without alloantibodies. Since monocytes play a critical role in polarization of T cell subsets and participate in clearance of transfused RBCs, we tested the hypothesis that in response to RBC breakdown product, hemin, monocyte control of T cell polarization will differ between alloimmunized and non-alloimmunized SCD patients. Exogenous hemin induced Treg polarization in purified T-cell-monocyte cocultures from healthy volunteers through monocyte anti-inflammatory heme degrading enzyme HO-1. Importantly, hemin primarily through its effect on CD16+ monocytes induced an anti-inflammatory (higher Treg/lower Th1) polarization state in non-alloimmunized SCD group, whereas it had little effect in the alloimmunized group. Non-alloimmunized SCD CD16+ monocytes expressed higher basal levels of HO-1. Furthermore, IL-12, which contributed to a pro-inflammatory polarization state (low Treg/high Th1) in SCD, was dampened in hemin-treated stimulated monocytes from non-alloimmunized SCD patients, but not in alloimmunized group. These data suggest that unlike alloimmunized patients, non-alloimmunized SCD CD16+ monocytes in response to transfused RBC breakdown products promote an anti-inflammatory state that is less conductive to alloimmunization.