Adiponectin is a negative regulator of antigen‐activated T cells

Abstract

Adiponectin (APN), a cytokine constitutively produced in fat tissue, has been shown to exert anti-inflammatory effects in various disease models. While the influence of APN on monocytic cells has been extensively studied in vitro, little is known about its role in T cells. In this study, we show that while o10% of human peripheral blood T cells express adiponectin receptors (AdipoRs) on their surface, most T cells store AdipoRs in intracellular compartments. AdipoRs colocalized with immune regulatory molecules CTLA-4 and TIRC7 within clathrin-coated vesicles. After stimulation, the expression of adiponectin receptor 1 (AdipoR1) and AdipoR2 was upregulated on the surface of antigen-specific T cells, as determined by tetramer or CD137 staining, and AdipoR1 and AdipoR2 coexpressed with CTLA-4. Addition of APN resulted in a significant diminution of antigenspecific T-cell expansion. Mechanistically, APN enhanced apoptosis and inhibited proliferation of antigen-specific T-cell lines. Further, APN directly inhibited cytokine production in response to antigen stimulation. In line with the in vitro data, APN-deficient (knockout, KO) mice had higher frequencies of CD137 1 T cells upon Coxsackie B virus infection. Altogether, our data suggest that APN is a novel negative T-cell regulator. In contrast to the CTLA-4 ligand B7 only expressed on APCs, APN is abundant in human plasma.

Adiponectin regulates psoriasiform skin inflammation by suppressing IL-17 production from γδ-T cells

“…Quantitative real-time PCR detected both AdipoR1 and AdipoR2 mRNA in dermal gd-T cells, although AdipoR2 protein expression was below the detection limit by western blot analysis. This result is consistent with the past reports demonstrating discrepancy between mRNA and protein levels of AdipoR2 in leukocytes 41,42 . Control experiments have revealed that AdipoR1 and AdipoR2 mRNA levels are reduced by 465% as evaluated by real-time reverse transcription-PCR analysis (Fig.…”

Adiponectin modulates NK‐cell function

“…1A, left, and C). In contrast, and as already shown in a recent study [8] less than 10% of CD3 + CD4 + T cells express surface AdipoRs expression (Fig. 1A, right).…”

“…However, the CD56 high subset expresses both receptors intracellularly. Human T cells do store AdipoRs in a similar manner intracellularly within Clathrin-coated vesicles together with CTLA-4 and surface unpregulation is induced by T-cell receptor stimulation [8]. In NK cells we could not induce AdipoRs surface expression by IL-2 or TLR stimulation.…”

“…In a recent study we could further demonstrate that T cells store AdipoRs intracellularly, upregulate them upon T-cell receptor activation, and that APN acts as a negative T-cell regulator for antigen-activated T cells [8]. Furthermore, APN has been described as a negative regulator of hematopoiesis inhibiting directly proliferation of myelomonocytic progenitors [12] or indirectly through inducing changes in stromal cells [13].…”

“…AdipoR1 is ubiquitous, but most prominent in skeletal muscle and heart, whereas AdipoR2 is abundantly expressed in the liver [6]. AdipoRs expression was further described in cells of the immune system [7,8]. Several studies revealed the direct action of APN on cells of the innate and adaptive immune system [1,9].…”