• CD4⁺CXCR3⁺ T cells and plasmacytoid dendritic cells enhanced atherosclerosis in patients with Systemic Lupus Erythematosus (SLE)

 SACRE K^1,2,3, Clément M⁴, Charles N^2,3, Escoubet B⁵, Guedj K⁴, Chauveheid MP¹, Ollivier V⁴, Caligiuri G^3,4, Nicoletti A^3,4; Papo T^1,2,3

1-Service de Médecine Interne, Hôpital Bichat, Université Paris Diderot, PRES Sorbonne Paris Cité, Assistance Publique Hôpitaux de Paris, Paris, France

2-INSERM U1149, Université Paris Diderot, Laboratoire d’excellence INFLAMEX, PRES Sorbonne Paris Cité, Paris, France

3-Département Hospitalo-Universitaire FIRE (Fibrosis, Inflammation and Remodelling in Renal and Respiratory Diseases), Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France

4-INSERM U1148, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France

5-Département de Physiologie, Hôpital Bichat, Université Paris Diderot, PRES Sorbonne Paris Cité, Assistance Publique Hôpitaux de Paris, Paris, France

 karim.sacre@bch.aphp.fr

 Introduction Cardiovascular disease (CVD) is a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). As atherosclerosis is itself immune-mediated, specific features of SLE-associated immunity might explain accelerated cardiovascular disease in this population. We herein investigated the role of T cells and plasmacytoid dendritic cells (pDCs) – both crucial in SLE pathogenesis – in atherosclerosis associated with SLE.

 Results We first observed that peripheral CD4⁺T cells expressing CXCR3, a chemokine receptor involved in recruitment of T cells in atherosclerotic lesions, were high in SLE patients and correlated with atherosclerosis, as assessed by measurements of carotid internal carotid artery wall thickness (ICWT). Such CD4⁺CXCR3⁺ T cells were antigen-primed and produced high levels of TNF-α. On the other hand, CXCR3 ligands (i.e. CXCL9, CXCL10, CXCL11) were high is SLE patients with active disease. In addition, IFN-α produced by pDCs upon TLR-9 stimulation induced both the in vitro expansion of CD4⁺CXCR3⁺ T cells and production of CXCR3 ligands by human coronary endothelial cells (HCEC). Eventually, TLR-9 stimulation 1-induced the development of anti-ssDNA autoantibodies and a significant rising of CXCL10 in serum, 2-enhanced CD4⁺CXCR3⁺ T cells recruitment in arterial wall, and 3-promoted atheroslerosis in apoE-/- mice.

 Conclusion SLE-associated atherosclerosis may be driven by a positive pathway in which IFN-α produced by pDCS promotes the expansion of a high frequency of antigen-stimulated, CD4⁺CXCR3⁺ T cells and induces endothelial cells to secrete CXCR3 ligands, which itself drive progressive infiltration of the arterial wall and atherosclerosis.