The Dendritic Cell Dilemma in the Skin: Between Tolerance and Immunity

Scheib, Nils; Tiemann, Jessica; Becker, Christian; Probst, Hans; Raker, Verena; Steinbrink, Kerstin

doi:10.3389/fimmu.2022.929000

Cited by 12 publications

(5 citation statements)

References 164 publications

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“…Since neither viral particles nor cell-cell contacts are strictly required to manipulate MDDC responsiveness, we then tested the conditioning ability of the supernatant of HTLV-1-infected T cells. More specifically, we hypothesized that IL-10 produced by HTLV-infected T cells 25 could be a candidate mediator, as it was reported to have tolerogenic properties 26 . However, except for the supernatant of the MT-2 infected T cell line, IL-10 was not detected in the supernatant of any of the other infected T cell lines ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Peculiar transcriptional reprogramming with functional impairment of dendritic cells upon exposure to transformed HTLV-1-infected cells

Carcone,

Mortreux,

Alais

et al. 2024

Preprint

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Manipulation of immune cell functions, independently of direct infection of these cells, emerges as a key process in viral pathophysiology. Chronic infection by Human T-cell Leukemia Virus type 1 (HTLV-1) is associated with immune dysfunctions, including misdirected responses of dendritic cells (DCs). Here, we interrogate the ability of HTLV-1-infected T cells to indirectly manipulate human DC functions. We show that upon coculture with chronically infected T cells, monocyte-derived DCs (MDDCs) fail to fully mature. We further show that exposure to HTLV-1-infected T cells induces a unique transcriptional signature in MDDCs, which differs from a typical maturation program, and which is correlated with a dampened ability of HTLV-1-exposed MDDCs to subsequently respond to restimulation. Induction of this tolerogenic behavior is not strictly dependent on capture of HTLV-1 viral particles by MDDCs, nor on cell-cell contacts between HTLV-1-infected T cells and MDDCs, but is instead the result of a molecular dialogue between HTLV-1-infected T cells and MDDCs upon coculture, illustrating how HTLV-1 might indirectly induce a local tolerogenic immune microenvironment suitable for its own persistence.

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Section: Resultsmentioning

confidence: 99%

Peculiar transcriptional reprogramming with functional impairment of dendritic cells upon exposure to transformed HTLV-1-infected cells

Carcone,

Mortreux,

Alais

et al. 2024

Preprint

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“…An outstanding question is where CAR-Tregs would encounter donor antigen and costimulation. Skin-resident APCs play an important role in the regulation of alloimmunity (76)(77)(78)(79), and in our immunocompetent skin graft model, these cells could deliver both CAR and costimulatory signals to CAR-Tregs. After activation in the allograft, Treg migration to dLNs is thought to be essential for establishing immune tolerance (80).…”

Section: Discussionmentioning

confidence: 96%

Tregs integrate native and CAR-mediated costimulatory signals for control of allograft rejection

Rosado-Sánchez,

Haque,

Salim

et al. 2023

JCI Insight

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Tregs expressing chimeric antigen receptors (CAR-Tregs) are a promising tool to promote transplant tolerance. The relationship between CAR structure and Treg function was studied in xenogeneic, immunodeficient mice, revealing advantages of CD28-encoding CARs. However, these models could underrepresent interactions between CAR-Tregs, antigen-presenting cells (APCs), and donor-specific Abs. We generated Tregs expressing HLA-A2–specific CARs with different costimulatory domains and compared their function in vitro and in vivo using an immunocompetent model of transplantation. In vitro, the CD28-encoding CAR had superior antigen-specific suppression, proliferation, and cytokine production. In contrast, in vivo, Tregs expressing CARs encoding CD28, ICOS, programmed cell death 1, and GITR, but not 4-1BB or OX40, all extended skin allograft survival. To reconcile in vitro and in vivo data, we analyzed effects of a CAR encoding CD3ζ but no costimulatory domain. These data revealed that exogenous costimulation from APCs can compensate for the lack of a CAR-encoded CD28 domain. Thus, Tregs expressing a CAR with or without CD28 are functionally equivalent in vivo, mediating similar extension of skin allograft survival and controlling the generation of anti–HLA-A2 alloantibodies. This study reveals a dimension of CAR-Treg biology and has important implications for the design of CARs for clinical use in Tregs.

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“…Other characteristic marker of DCs that were analyzed in this study were CD141, which is expressed on conventional DC-type 1 (cDC1), and CD303, a marker for plasmacytoid DCs (pDCs) (Fig. 4) [7,26,33,49]. The density of CD141 + -and CD303 + -cells was signi cantly decreased in non-lesional zones of the dermis of psoriasis patients compared to healthy skin (Fig.…”

Section: Impact Of Treatment With Adalimumab or Ixekizumab On Low-den...mentioning

confidence: 94%

Regulation of the Immune Cell Repertoire in Psoriasis Patients Upon Blockade of IL-17A or TNFα

Tittes

Brell

Fritz

et al. 2023

Preprint

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Targeting of the pro-inflammatory cytokines interleukin 17A (IL-17A) or tumor necrosis factor alpha (TNFα) with monoclonal antibodies (mAbs) ixekizumab or adalimumab, respectively, are successful therapies in chronic plaque psoriasis. The effects of these treatments on immune cell populations in the skin are largely unknown. In this study, we compared the composition of cutaneous, lesional as well as non-lesional, and blood immune cells in ixekizumab or adalimumab treated patients with psoriasis. Our data reveal that both treatments efficiently down-regulate T-cells, macrophages and different subsets of dendritic cells (DCs) in lesional skin towards levels of healthy skin. In contrast to lesional skin, non-lesional areas in patients harbor only few or no detectable DCs compared to skin of healthy subjects. Neither the treatment with ixekizumab nor adalimumab reverted this DC imbalance in non-lesonal skin of psoriatic patients. Taken together, our study shows that anti-IL-17A as well as anti-TNFα therapy rebalances the immune cell repertoire of lesional skin in psoriatic patients, but fail to restore the disturbed immune cell repertoire in non-lesional skin during the induction phase of therapy.

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The Dendritic Cell Dilemma in the Skin: Between Tolerance and Immunity

Cited by 12 publications

References 164 publications

Peculiar transcriptional reprogramming with functional impairment of dendritic cells upon exposure to transformed HTLV-1-infected cells

Peculiar transcriptional reprogramming with functional impairment of dendritic cells upon exposure to transformed HTLV-1-infected cells

Tregs integrate native and CAR-mediated costimulatory signals for control of allograft rejection

Regulation of the Immune Cell Repertoire in Psoriasis Patients Upon Blockade of IL-17A or TNFα

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