Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists

Monocytes can develop into dendritic cells (DCs) that migrate to lymph nodes (LNs) and present antigens to T cells. However, we find that this differentiation is blocked when monocytes accumulate subcutaneously in response to bacteria or lipopolysaccharide (LPS). The inhibition of DC differentiation is mediated by the bacteria and in conjunction with inflammatory cells recruited at the site of injection. Inhibition of migratory DC development was reversed in Toll-like receptor (TLR)4-mutated mice when LPS, but not whole bacteria, was injected, suggesting that TLR4 is one but not the only mediator of the inhibition. The block imposed by bacteria was partly relieved by the absence of interleukin (IL)-12 p40, but not by individual absence of several cytokines involved in DC differentiation or in inflammation, i.e., IL-6, IL-10, IL-12 p35, and interferon γ. Consistent with the inability of monocytes to yield migrating DCs, and the finding that other DCs had limited access to particulate or bacterial antigens, these antigens were weakly presented to T cells in the draining LN. These results illustrate that bacteria-associated signals can have a negative regulatory role on adaptive immunity and that local innate responses for containment of infectious bacteria can at least initially supersede development of adaptive responses.

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The paracaspase MALT1 in psoriasis

Biological Chemistry ◽

10.1515/hsz-2021-0250 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Stephan Hailfinger ◽

Klaus Schulze-Osthoff

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Transcription Factors ◽

Skin Disease ◽

Cell Types ◽

Cytokine Receptors ◽

Molecular Scaffold ◽

Therapeutic Implications ◽

Stimulation Of

Abstract Psoriasis is a frequent autoimmune-related skin disease, which involves various cell types such as T cells, keratinocytes and dendritic cells. Genetic variations, such as mutations of CARD14, can promote the development of the disease. CARD14 mutations as well as the stimulation of immune and cytokine receptors activate the paracaspase MALT1, a potent activator of the transcription factors NF-κB and AP-1. The disease-promoting role of MALT1 for psoriasis is mediated by both its protease activity as well as its molecular scaffold function. Here, we review the importance of MALT1-mediated signaling and its therapeutic implications in psoriasis.

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Stimulation of autologous proliferative and cytotoxic T-cell responses by “leukemic dendritic cells” derived from blast cells in acute myeloid leukemia

Blood ◽

10.1182/blood.v97.9.2764 ◽

2001 ◽

Vol 97 (9) ◽

pp. 2764-2771 ◽

Cited By ~ 77

Author(s):

Beth D. Harrison ◽

Julie A. Adams ◽

Mark Briggs ◽

Michelle L. Brereton ◽

John A. Liu Yin

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Dendritic Cells ◽

T Cell ◽

Myeloid Leukemia ◽

T Cell Responses ◽

Cell Responses ◽

Antigen Presenting ◽

Acute Myeloid ◽

Stimulation Of

Abstract Effective presentation of tumor antigens is fundamental to strategies aimed at enrolling the immune system in eradication of residual disease after conventional treatments. Myeloid malignancies provide a unique opportunity to derive dendritic cells (DCs), functioning antigen-presenting cells, from the malignant cells themselves. These may then co-express leukemic antigens together with appropriate secondary signals and be used to generate a specific, antileukemic immune response. In this study, blasts from 40 patients with acute myeloid leukemia (AML) were cultured with combinations of granulocyte-macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor α, and development to DCs was assessed. After culture, cells from 24 samples exhibited morphological and immunophenotypic features of DCs, including expression of major histocompatibility complex class II, CD1a, CD83, and CD86, and were potent stimulators in an allogeneic mixed lymphocyte reaction (MLR). Stimulation of autologous T-cell responses was assessed by the proliferative response of autologous T cells to the leukemic DCs and by demonstration of the induction of specific, autologous, antileukemic cytotoxicity. Of 17 samples, 11 were effective stimulators in the autologous MLR, and low, but consistent, autologous, antileukemic cytotoxicity was induced in 8 of 11 cases (mean, 27%; range, 17%-37%). This study indicates that cells with enhanced antigen-presenting ability can be generated from AML blasts, that these cells can effectively prime autologous cytotoxic T cells in vitro, and that they may be used as potential vaccines in the immunotherapy of AML.

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