AB0043 Regulatory Function of Natural Killer Cells in Systemic Lupus Erythematosus (SLE)

Abstract

Background Natural killer (NK) cells are large granular lymphocytes that belong to the innate immunity. The activation or inhibition of NK cells is regulated by several membrane receptors, commonly designated as NK cell receptors (NKR). Despite its well-known functions it has been recently reported that NK cells are also involved in the regulation of the adaptive immune response. The NK regulatory mechanisms include the acquisition of MHC class II and costimulatory molecules to sub-optimal levels in order to induce T cell anergy. Moreover, it has been found that NK cells are able to inhibit T cell proliferation by lysing dendritic cells (DC). Systemic lupus erythematosus (SLE) is an autoimmune disease, which results from numerous immunological abnormalities. It has been described that SLE patients display impairment in both, the levels and the cytotoxic function of NK cells. However, NK cells regulatory function in SLE has not been evaluated. Objectives We aim to study the NKR and costimulatory molecules expression in NK cells from SLE patients, as well as its inhibitory function. Methods Fifteen SLE patients according to the classification criteria of the American College of Rheumatology and seven healthy controls have been included. The expression of NKG2D, NKG2C, NKG2A, NKp46, NKp30, ILT2, CD161, and costimulatory molecules: CD80, CD86, HLA-DR, CD134 (OX40), was evaluated in peripheral blood NK cells (CD3-CD56+) by multiparametric flow cytometry. In order to evaluate the inhibitory function of NK cells, we performed co-cultures with NK cells and autologous, CFSE loaded, immature DC or mature DC as targets cells; co-cultures were done at different NK cells–DC ratios (0:1, 1:5, 5:1, 1:0) for 24h and 48 h; the percentage of DC lysis was assessed by flow cytometry. Results We found that SLE patients show a similar pattern of NKR expression than healthy controls. However, the inhibitory receptor ILT2 and the activator NKR, NKp30 and NKG2C, showed a slight increase in their expression. Furthermore, we observed that the expression of the costimulatory molecules CD80, CD86 and CD134, as well as HLA-DR was increased in SLE patients compared to healthy controls. In addition, we found that NK from SLE patients are less capable to lyse immature DC compared with control NK cells. In contrast, NK cells from SLE patients are more efficient lysing mature DC compared with controls. Conclusions Our results suggest that NK cells from SLE patients show an activating phenotype, which, in addition to the high expression of HLA-DR and costimulatory molecules provides them with the ability to present antigens and activate T cells. Furthermore, NK cells from SLE patients do not lyse immature DC efficiently, which may promote the presentation of auto-antigens by DC resulting in the activation of autoreactive T cells. All the above may contribute to SLE pathogenesis. References Novel APC-like properties of human NK cells directly regulate T cell activation. Hanna J, et al. J Clin Invest 2004; 114:1612-1623. Natural killer (...