Abstract
BACKGROUND
Spondyloarthritis (SpA) is a chronic inflammatory disorder with axial and peripheral manifestations. A strong association between HLA-B27 and SpA has been known for more than 50 years. Remarkably, HLA-B27 and human β2-microglubulin transgenic rats (B27 rat) develop manifestations recapitulating SpA, referred to as rat SpA. Antigen-presenting cells such as dendritic cells (DC) and CD4 T cells are mandatory to develop rat SpA. Serum levels of granulocyte macrophage-colony stimulating factor (GM-CSF), a key growth factor for DC generation and functions, are significantly increased during SpA. Conventional (c)DCs can be divided in two subsets implicated either in immune tolerance (cDC1) or in adaptive immune responses induction (cDC2). In this study, we aimed to determine the influence of GM-CSF on cDC subsets functions linked to T cell activation and differentiation, in the B27 rat model.
METHODS
cDC subsets were isolated from spleens of B27 and nontransgenic (NTG) rats, primed with GM-CSF and tested for their ability to support CD4h T cell differentiation. RNA sequencing was performed on GM-CSF-primed cDC subsets.
RESULTS
GM-CSF-primed cDC2 from B27 rat were strong inducers of TNF-producing proinflammatory CD4+ T cells. In contrast, whereas control cDC1 required GM-CSF to support T cell proliferation, HLA-B27+ cDC1 primed with GM-CSF failed to do so. RNA sequencing analysis demonstrated that HLA-B27 expression promoted endoplasmic reticulum stress and unfolded protein response in both cDC subsets. In addition, HLA-B27 expression promoted inflammatory cytokine synthesis by cDC2 and a signature interfering with regulation of cell adhesion and activation in cDC1.
CONCLUSION
Altogether, our study reveals a dual role of GM-CSF during SpA. In one hand, GM-CSF promotes proinflammatory functions of cDC2. On the other hand, GM-CSF is required for cDC1 to induce T cell proliferation, and those functions are blunted by HLA-B27 expression.
