ABSTRACT
Dopamine has emerged as an important regulator of immunity. Recent evidence has shown that signalling through low-affinity dopamine receptors exerts anti-inflammatory effects, whilst stimulation of high-affinity dopamine receptors potentiates immunity in different models. However, the dopaminergic regulation of CD8+ T-cells in anti-tumour immunity remains poorly explored. Here, we studied the role of dopamine receptor D3 (DRD3), which displays the highest affinity for dopamine, in the function of CD8+ T-cells and its consequences in the anti-tumour immune response. We observed that the deficiency of Drd3 (the gene encoding DRD3) in CD8+ T-cells limits their in vivo expansion, leading to an impaired anti-tumour response in a mouse melanoma model. Mechanistic analyses suggest that DRD3 stimulation favours the production of interleukin 2 (IL-2) and the surface expression of CD25, the α-chain IL-2 receptor, which are required for expansion and effector differentiation of CD8+ T-cells. Thus, our results provide genetic and pharmacologic evidence indicating that DRD3 favours the production of IL-2 by CD8+ T-cells, which is associated with higher expansion and acquisition of effector function of these cells, promoting a more potent anti-tumour response in a melanoma mouse model. These findings contribute to understanding how dopaminergic signalling affects the cellular immune response and represent an opportunity to improve melanoma therapy.
Subject(s)
Melanoma , T-Lymphocytes, Cytotoxic , Animals , Mice , CD8-Positive T-Lymphocytes , Disease Models, Animal , Dopamine , Interleukin-2/metabolism , Receptors, Dopamine , T-Lymphocytes, Cytotoxic/metabolismABSTRACT
Collagen IV has been described as a structural protein of the basement membrane, which as a whole forms a specialized extracellular matrix. Recent studies have indicated a possible relationship between collagen IV and the innate immune response of invertebrate organisms. The present study characterized the alpha-1 chain of collagen IV in the red abalone Haliotis rufescens (Hr-ColIV) and evaluated its association with the innate immune response against Vibrio anguillarum. To further evidence the immune response, the matrix metalloproteinase-1 (Hr-MMP-1) and C-type lectin (Hr-CLEC) genes were also assessed. The complete sequence of Hr-ColIV was composed of 6658 bp, with a 5'UTR of 154 bp, a 3'UTR of 1177 bp, and an ORF of 5327 bp that coded for 1776 amino acids. The innate immune response generated against V. anguillarum resulted in a significant increase in the transcript levels of Hr-ColIV between 3 and 6 hpi, whereas Hr-MMP-1 and Hr-CLEC had the highest transcript activity 6 and 12 hpi, respectively. The results obtained in this study propose a putative biological function for collagen IV involved in the early innate immune response of the red abalone H. rufescens.