Intravenous immunoglobulin (IVIg) inhibits CD8 cytotoxic T-cell activation

Abstract

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...

Gene Expression Profiling in Peripheral Blood Mononuclear Cells of Patients with Common Variable Immunodeficiency: Modulation of Adaptive Immune Response following Intravenous Immunoglobulin Therapy

“…Such modifications include the expansion of CD4+ helper T cells and the reduction of CD8+ cytotoxic T cells. This effect on CD8+T cells is in accordance with recent findings in animal models [28], [29]; indeed IVIg treatment has been reported to decrease in vitro response of antigen specific CD8+T cells, suggesting a similar mechanism in vivo in patients with inflammatory and autoimmune diseases, characterized by self-reactive cytotoxicity [30].…”

Polyclonal immunoglobulin G for autoimmune demyelinating nervous system disorders

“…Polyclonal IgG has profound effects on both T and B lymphocytes, the key cellular components of the adaptive immune system. It may skew peripheral blood T cell subsets in multiple beneficial ways, including suppression of pro-inflammatory Th17 cells [25][26][27], promotion of protective CD4/CD25/FoxP3-positive T regulatory cells [28][29][30][31][32], induction of a protective Th1/Th2 shift [33][34][35], and inhibition of CD8-positive cytotoxic T cell activation and expansion [36,37]. Importantly, polyclonal IgG may inhibit T cell interactions with antigen-presenting cells by binding to T cell surface receptors, including the T cell receptor b-chain, HLA molecules, and costimulatory molecules such as CD28 [38][39][40][41].…”

Mannosylated lipopetides as model vaccines for targeting the mannose receptor

“…It is also argued that this epitope also bears at least one B cell epitope (323)(324)(325)(326)(327)(328)(329)(330)(331)(332)(333)(334)(335)(336)(337)(338)(339), however, there is only one study that has mentioned the presence of the B cell epitope [327]. In a study by Sun et al, it was shown that 50% of the B cell response generated by the OVA protein was antibody specific to the OVA323-339 epitope [327].…”

“…In a study by Sun et al, it was shown that 50% of the B cell response generated by the OVA protein was antibody specific to the OVA323-339 epitope [327]. As the vaccine structures (G1-6) contain the CD4 epitope (OVA [323][324][325][326][327][328][329][330][331][332][333][334][335][336][337][338][339], the in vivo ability of vaccine structures (G1-9) for a T cell activation proliferation was assessed. Here, OT-II proliferating cells are considered to be activated when T cells expressing CD45.2 increase in percentage over the total parental CD4 + T cells [329].…”

“…The OVA protein naturally exists as a glycoprotein, however, it was discovered that the OVA [323][324][325][326][327][328][329][330][331][332][333][334][335][336][337][338][339] and OVA 1-10 sequences of the OVA protein bore a B cell epitope that was capable of inducing a T cell response. This discovery was obtained by T cell mediated IgE responses that were observed against an assumed B cell epitope inside OVA323-339 and OVA1-10 peptides [185].…”