AB0026 Immune Complexes Trigger Differentiation of Human Peripheral Naïve CD4+ T Cells
Authors: C. Chen, Y. Bi, T.L. Moore, A.K. Chauhan
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> T cells contribute to the disease process in systemic lupus erythematosus (SLE) (1-3). IFN-γ is a cytokine produced by the Th1 subset that drives autoimmune pathology (4, 5). IFN-γ produced during Th1 response via autocrine process regulates its own expression and also of the transcriptional regulator T-bet (<i>Tbx21</i>). In an autoimmune pathology, CD4<sup>+</sup> T cells are activated in the absence of co-stimulatory CD28 signal. The underlying mechanism of this activation is unknown. We show that engagement of low affinity FcγRIIIa from ligation by immune complexes (ICs) provide a co-stimulatory signal that drive the generation of a high IFN-g producing subset and a Th17 like population. We for the first time establish a role for FcgRIIIa in modulating the adaptive immune response. IFN-γ is a key cytokine that enhance B cell response, activate macrophages, and chromatin remodeling <h3>Objectives</h3> To investigate the role of ICs in CD4<sup>+</sup> naïve T cells differentiation. <h3>Methods</h3> We activated peripheral naïve CD4<sup>+</sup>CD45RA<sup>+</sup> T cells in vitro using ICs purified from SLE plasma. Thereafter, we differentiated these cells in the presence of IL-2 (2 U/ml) and IL-12 (50 U/ml) cytokines. We then examined the production of IFN-γ by flow, and in the culture supernatants. Gene transcripts of <i>ifng</i> and <i>Tbx21</i> were analyzed using qRT-PCR. IFN pathway genes were analyzed using PCR-array. We further examined the role of ICs in the differentiation Th17 cells, in the presence of IL-1b, IL-6, IL23, and TGFβ-1 cytokines. <h3>Results</h3> We show that upon activation by ICs human peripheral CD4<sup>+</sup> T-lymphocytes differentiate into a Th1 like cell phenotype that produces high levels of IFN-γ and express T-bet. All five donors analyzed demonstrate increases in <i>ifng</i> and <i>Tbx21</i> transcripts. IFN pathway genes showed several folds from 3 to 20-fold increase in the transcript9s associated with IFN signaling. One donor also showed expression of type 1 IFN transcripts that were further up-regulated from ICs signaling. The presence of type 1-IFN transcripts in CD4<sup>+</sup> T cells has not been previously demonstrated. The co-stimulatory signal by ICs was more potent than CD28 for the production of IFN-g. In the Th17 polarizing milieu, three subsets of population was observed, IFN-γ<sup>+</sup>IL17A<sup>-</sup>, IFN-γ<sup>-</sup>IL-17A<sup>+</sup>, and IFN-γ<sup>+</sup>IL-17<sup>+</sup>. Increase in <i>RORC</i> transcripts were also observed. <h3>Conclusions</h3> We for the first time demonstrate a role for FcgRIIIa in the differentiation of the human peripheral naïve CD4<sup>+</sup> T cells. ICs by ligating FcgRIIIa generated both Th1 and Th17 like populations, thus suggesting a role in autoimmune pathology. <h3>References</h3> Konya C, Paz Z, Tsokos GC. The role of T cells in systemic lupus erythematosus: an update. Current Opinion in Rheumatology, 2014, 26(5): 493-501. Smith-Garvin JE, Koretzky GA, Jordan MS. T cell activation. Annual Review of Immunology, 2009, 27: 591. Crispín JC, Kyttaris VC, Terhorst C, et al. T cells as therapeutic targets in SLE. Nature Reviews Rheumatology, 2010, 6(6): 317-325. Pollard KM, Cauvi DM, Toomey CB, et al. Interferon-γ and systemic autoimmunity. Discov Med. 2013, 16(87):123-31. Lazarevic V, Glimcher LH. T-bet in disease. Nature Immunology, 2011, 12(7): 597-606. <h3>Disclosure of Interest</h3> None declared