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References 1. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. 2. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798. 3. Verstovsek S, Kantarjian HM, Estrov Z, et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. We recently reported that intravenous immunoglobulin (IVIg) interferes with the binding of ovalbumin immune complexes (OVA-IC) to phagocytic FcRs, leading to a decreased internaliza-tion inside antigen-presenting cells (APCs) and resulting in a reduced amount of antigen presented by MHC II molecules to CD4 helper T cells. 1 Consequently, the antigen-specific helper T-cell response is dampened in the presence of IVIg. In the context of autoimmune diseases, these observations suggest that IVIg treatment could decrease the presentation of self-antigens to CD4 T cells and prevent the subsequent autoantibody production. Although CD8 cytotoxic T cells play a substantial role in organ destruction in several autoimmune diseases, 2-4 the effect of IVIg on this cell compartment has not been studied so far. We hypothesized that CD8 T-cell activation could be impaired in the presence of IVIg, by a mechanism similar to that described for CD4 T-cell activation. We thus used OT-II (CD4) I-Ab-restricted OVA-specific primary T cells 5 to first confirm that the previously reported inhibitory effect of IVIg was not limited to I-Ad-restricted OVA-specific CD4 T cells (DO-11.10). 1 We also used OT-I (CD8) H2K b-restricted OVA-specific T cells 6 to determine the effect of IVIg on the ability of APCs to activate CD8 T cells by cross-presentation of OVA-IC. OT-I and OT-II cells were purified from the spleen and lymph nodes of C57BL/6-Tg(TcraTcrb)1100Mjb/J and B6.Cg-Tg(TcraTcrb)425Cbn/J mice, respectively. Bone marrow-derived dendritic cells (BMDCs) from C57BL/6 mice were prepared as previously described 1 and used as APCs to activate OT-I and OT-II cells in the presence of OVA-IC, with or without IVIg. T-cell activation was determined by flow cytometry using CD69 expression as a marker of cell activation. 7 Our results first show an increased proportion of OT-II cells expressing CD69 after OVA-IC presentation, from a background level of 3% up to 74% (Figure 1 top left and middle panels). When IVIg was present during OVA-IC presentation, the percentage of cells expressing CD69 only reached 10% (Figure 1 top right panel), indicating that OT-II cell activation was significantly impaired in the presence of IVIg. The inhibitory effect of IVIg on OT-II cell activation is thus similar to that previously observed with DO-11.10 cells, regardless of their different MHC restriction profile. Our results also reveal the efficient activation of OT-I cells by OVA-IC cross-presentation, as shown by the increase from a backg...

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SummaryIntravenous immunoglobulin (IVIg) is successfully used in the treatment of autoimmune diseases involving self-reactive CD8 + T cells. However, its direct influence on the cytotoxic response remains unknown. Using an antigen cross-presentation assay and a mouse model of ovalbumin (