Natural killer (NK) cells participate in the regulation of the immune response. However, the immunomodulatory function of NK cells in systemic lupus erythematosus (SLE) is not well understood. The aim of this study was to evaluate the regulatory function of NK cells in SLE patients and to identify the NK cells involved in the pathogenesis of this complex disease. We analysed the expression of NK receptors and co-stimulatory molecules in peripheral NK cells (CD3 CD56 ) from SLE patients, as well as the numbers of human leucocyte antigen D-related (HLA-DR)/CD11c NK cells. In addition, NK cell regulatory function was assessed by the detection of NK cell-mediated dendritic cell (DC) lysis. We found that SLE patients showed increased numbers of immunoglobulin-like transcript 2 (ILT2) , CD86 and CD134 NK cells. Furthermore, NK cells from SLE patients induced higher levels of DC lysis. We were able to identify a new subset of NK cells co-expressing CD11c and HLA-DR. These atypical NK cells were increased in SLE patients when compared with controls. We have identified an expanded new subset of NK cells in SLE patients. This is the first study, to our knowledge, which demonstrates that NK cells in SLE patients have an altered phenotype with a high expression of receptors characteristic of dendritic cells. Our results suggest that the impairment in the regulatory function of NK cells, together with the increased number of DC-like NK cells, could play an important role in the development of SLE and highlight the importance of NK cells as a future therapeutic target.

Dendritic cells (DC) play an important role in the development and maintenance of immune tolerance. Although the inhibitory receptor ILT4/LILRB2 has been related with the tolerogenic phenotype of DC, the possible role of this receptor in the breakdown of DC tolerogenic function in systemic lupus erythematosus (SLE) has not been elucidated. In this study, we analyzed the expression and function of the inhibitory receptor ILT4 in DC from SLE patients. We found that the percentage of ILT4 positive plasmacytoid DC and myeloid DC is significantly diminished in SLE patients. Interestingly, ligation of ILT4 did not affect the maturation or immunogenic capability of DC in healthy controls. In contrast, in SLE patients we observed an inhibitory effect of ILT4 on the immunogenic capability of DC. ILT4 was shown not to have a crucial role in regulating the maturation and function of DC from healthy controls but is partially involved in the maturation process and immunogenic capability of DC from SLE patients, suggesting that other inhibitory receptors, involved in the regulation of DC tolerogenic function, may be impaired in this autoimmune disease.

Dendritic cells (DCs) and regulatory T cells (Tregs) play an essential role in myocarditis. However, a particular DC phenotype in this disease has not been assessed. Herein, we aim to evaluate myeloid (mDCs) and plasmacytoid DC (pDC) phenotype, as well as Treg levels from myocarditis patients and healthy controls. Using multiparametric flow cytometry, we evaluated the levels of myeloid DCs (mDCs), plasmacytoid DCs (pDCs), and Tregs in peripheral blood from myocarditis patients ( n = 16 ) and healthy volunteers ( n = 16 ) and performed correlation analysis with clinical parameters through Sperman test. DCs from myocarditis patients showed a higher expression of costimulatory molecules while a diminished expression of the inhibitory receptors, ILT2 and ILT4. Even more, Treg cells from myocarditis patients displayed higher levels of FOXP3 compared to controls. Clinically, the increased levels of mDCs and their higher expression of costimulatory molecules correlate with a worse myocardial function, higher levels of acute phase reactants, and higher cardiac enzymes. This study shows an activating phenotype of circulating DCs from myocarditis patients. This proinflammatory status may contribute to the pathogenesis and immune deregulation in acute myocarditis.

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 (...