Expression of a soluble form of CTLA4 on macrophage and its biological activity

Gao, Yangfei; Wang, Pichao; Takagi, Katsuyuki; Shimozato, Osamu; Yagita, Hideo; Okigaki, Tohru; Matasumura, Masatoshi

doi:10.1038/sj.cr.7290017

Cited by 8 publications

(4 citation statements)

References 29 publications

(28 reference statements)

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“…However, in recipient mice that received Tregs from donor CS-exposed mice, we found fewer CTLA-4 + DC. CTLA-4 has been previously reported on macrophages ( Hua et al., 1999 ; Wang et al., 2002 ) and dendritic cells ( Wang et al., 2011 ) and may play a role in inhibiting immune response. Thus, this finding seems paradoxical since fewer CTLA-4 + DC would be expected not to inhibit CD4 + T effector cell as much, and thus would have relatively greater host immunity against MTB ( Laurent et al., 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Ex vivo and in vivo evidence that cigarette smoke-exposed T regulatory cells impair host immunity against Mycobacterium tuberculosis

Bai,

Verma,

Garcia

et al. 2023

Front. Cell. Infect. Microbiol.

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IntroductionA strong epidemiologic link exists between cigarette smoke (CS) exposure and susceptibility to tuberculosis (TB). Macrophage and murine studies showed that CS and nicotine impair host-protective immune cells against Mycobacterium tuberculosis (MTB) infection. While CS and nicotine may activate T regulatory cells (Tregs), little is known about how CS may affect these immunosuppressive cells with MTB infection.MethodsWe investigated whether CS-exposed Tregs could exacerbate MTB infection in co-culture with human macrophages and in recipient mice that underwent adoptive transfer of Tregs from donor CS-exposed mice.ResultsWe found that exposure of primary human Tregs to CS extract impaired the ability of unexposed human macrophages to control an MTB infection by inhibiting phagosome-lysosome fusion and autophagosome formation. Neutralizing CTLA-4 on the CS extract-exposed Tregs abrogated the impaired control of MTB infection in the macrophage and Treg co-cultures. In Foxp3+GFP+DTR+ (Thy1.2) mice depleted of endogenous Tregs, adoptive transfer of Tregs from donor CS-exposed B6.PL(Thy1.1) mice with subsequent MTB infection of the Thy1.2 mice resulted in a greater burden of MTB in the lungs and spleens than those that received Tregs from air-exposed mice. Mice that received Tregs from donor CS-exposed mice and infected with MTB had modest but significantly reduced numbers of interleukin-12-positive dendritic cells and interferon-gamma-positive CD4+ T cells in the lungs, and an increased number of total programmed cell death protein-1 (PD-1) positive CD4+ T cells in both the lungs and spleens.DiscussionPrevious studies demonstrated that CS impairs macrophages and host-protective T effector cells in controlling MTB infection. We now show that CS-exposed Tregs can also impair control of MTB in co-culture with macrophages and in a murine model.

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Section: Discussionmentioning

confidence: 99%

Ex vivo and in vivo evidence that cigarette smoke-exposed T regulatory cells impair host immunity against Mycobacterium tuberculosis

Bai,

Verma,

Garcia

et al. 2023

Front. Cell. Infect. Microbiol.

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“…The in vitro CTLA-4-Ig concentrations to be tested were chosen on the basis of the available literature, suggesting values that are very close to the therapeutic doses used to treat RA [22,24,25]. The macrophage/T cell ratio was 1:1.…”

Section: Methodsmentioning

confidence: 99%

CTLA4-Ig interacts with cultured synovial macrophages from rheumatoid arthritis patients and downregulates cytokine production

et al. 2009

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IntroductionCo-stimulatory signal B7(CD80/CD86):CD28 is needed in order to activate T cells in immune response. Cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (CTLA4-Ig) binding to the B7 molecules on antigen-presenting cells downregulates this activation and represents a recent biological treatment in rheumatoid arthritis (RA). Objectives of the study were to investigate the presence of the B7.2 (CD86) molecule and its masking by CTLA4-Ig on cultures of both RA synovial macrophages (RA SM), and of macrophages differentiated from THP-1 cells (M). In addition, the anti-inflammatory effects of CTLA4-Ig on co-cultures of RA SM and M with activated T cells were tested.MethodsAll macrophages were co-cultured for 24 hours with activated T cells, without or with CTLA4-Ig (10, 100, 500 μg/ml for 1 hour, 3 hours and overnight, respectively). Immunofluorescence (IF) staining for B7.2, and an analysis of inflammatory cytokine expression (interleukin (IL) -6, tumor necrosis factor (TNF) α, IL-1β, transforming growth factor (TGF) β) by immunocytochemistry (ICC), western blot (WB) and reverse transcriptase-polymerase chain reaction (RT-PCR) were performed.ResultsMacrophages showed intense B7.2 expression. CTLA4-Ig/B7.2 masking was evident for all macrophages, even after only 1 hour of cell culture (range from 10 to 100 μg/ml). ICC of co-cultures showed a dose-dependent decrease in inflammatory cytokines (P < 0.001 for IL-6, TNFα, IL-1β and TGFβ). Data were confirmed by WB and RT-PCR analysis.ConclusionsOptimal concentrations of CTLA4-Ig for the CTLA4-Ig/B7.2 masking on activated macrophages were identified and were found to induce significant downregulation in the cell production of IL-6, TNFα, IL1-β and TGFβ. In conclusion, macrophages would appear to be a sensitive target for CTLA4-Ig treatment in RA.

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“…In contrast to this early paradigm, other studies over the last two decades have demonstrated both constitutive and inducible expression of CTLA-4 in a broad distribution of tissues and cell types other than lymphocytes, particularly dendritic cells [ 14 ], human breast tumor cells [ 15 ], and macrophages [ 16 ]. Of special interest is the paper by Pistillo et al [ 17 ], who first described the reactivity and function of CTLA-4 in different cell types.…”

Section: Introductionmentioning

confidence: 99%

Identification of CTLA-4-Positive Cells in the Human Tonsil

Tiemann

Atiakshin

Samoilova

et al. 2021

Cells

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CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) was originally defined as a T-lymphocyte antigen and was used as a target in cancer immunotherapy. Unfortunately, the existence of CTLA-4 in cells other than T-lymphocytes is often overlooked. The goal of the present study was to analyze the distribution pattern of CTLA-4 in the human tonsils using a panel of anti–CTLA-4 antibodies of different clones. We found that CTLA-4 was expressed in T-lymphocyte cells of various geneses, including hematopoietic cells and their derivatives (monocytes, macrophages, dendritic, plasma cells, mast cells, and neutrophils), as well as stromal cells of mesodermal (mesenchymal) origin and reticular epithelial cells of ectodermal origin. The expression of CTLA-4 in cells of different origins supports the proposition that CTLA-4 is not restricted to the lymphoid cell lineage and can provide broader effects of CTLA-4 on immune regulation.

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Expression of a soluble form of CTLA4 on macrophage and its biological activity

Cited by 8 publications

References 29 publications

Ex vivo and in vivo evidence that cigarette smoke-exposed T regulatory cells impair host immunity against Mycobacterium tuberculosis

Ex vivo and in vivo evidence that cigarette smoke-exposed T regulatory cells impair host immunity against Mycobacterium tuberculosis

CTLA4-Ig interacts with cultured synovial macrophages from rheumatoid arthritis patients and downregulates cytokine production

Identification of CTLA-4-Positive Cells in the Human Tonsil

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