Session Title: T-cell Biology and Targets in Autoimmune Disease
Session Type: Abstract Submissions (ACR)
Background/Purpose: We have previously shown that B6 mice with an introgressed homozygous New Zealand Black chromosome (c) 1 interval (70 to 100 cM) develop high titres of antinuclear antibodies and severe glomerulonephritis (GN), with approximately 40% of the mice dying by 8 months age. Using subcongenic mice with shorter intervals in this region we found that expansion of TH1, TH17, and TFH cell populations was closely associated with the severity of GN. We further showed, using ovalbumin (OVA) as an exogenous antigen, that this was an intrinsic aspect of their immune system, resulting from a combination of T and non-T cell defects. In this report, we have investigated the role of dendritic cells (DC) in this expansion.
Methods: OVA-specific T cells from B6 or c1(70-100), c1(88-100), or c1(96-100) congenic OT-II TCR transgenic mice were adoptively transferred into B6.Thy1.1 or c1(70-100).Thy1.1 mice. Mice were immunized with OVA emulsified in CFA, sacrificed 2 weeks later, and the proportion of various splenic T cell subsets determined by flow cytometry, gating separately on Thy1.1+ (recipient) and Thy1.2+(transferred) T cells. Bone marrow-derived dendritic cells (DC) isolated from 8wk old c1(70-100), c1(88-100) and c1(96-100) congenic, and B6 control mice were cultured in the presence of LPS, imiquimod or CpG, or pulsed with OVA and co-cultured with naïve OT-II T cells. Production of cytokines (IL-12, IL-23, IL-6) by stimulated DC was analyzed by ELISA or flow cytometry.
Results: Adoptive transfer experiments revealed that the increased IFN-γ and IL-17 secreting cell differentiation in c1(70-100) congenic mice arises in part from intrinsic T cell defects localizing to the NZB c1 96-100 cM and 88-96 cM intervals, respectively. However, OT-II T cells from all mouse strains examined demonstrated enhanced differentiation to TH1, TH17, and TFHpopulations when transferred into c1(70-100).Thy1.1 as compared to B6.Thy1.1 mice. This finding suggested that the increased differentiation of these T cell subsets in c1 congenic mice was also dependent upon cellular and/or cytokine cues provided by the c1(70-100) environment. Since, DC play an important role in the antigen presentation and cytokine secretion that directs T cell responses, DC function was contrasted in the various mouse strains. Following TLR stimulation, DC from c1(70-100) mice expressed significantly higher levels of MHC and co-stimulatory molecules, and secreted higher amounts of pro-inflammatory cytokines such as IL-6 and IL-12. Consistent with altered DC function, OVA-pulsed DC from c1(70-100) mice induced significantly increased differentiation of naïve OT-II cells to IFN-γ, IL-17 or IL-21 secreting cells as compared to B6 DC.
Conclusion: Our results suggest that a genetic polymorphism in the 70-88 cM interval of NZB c1 congenic mice alters DC function and acts together with intrinsic T cell defects to promote the expansion of TH1, TH17 and TFH cells in c1(70-100) mice, resulting in severe GN.
N. H. Chang,
J. E. Wither,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-genetic-polymorphism-on-new-zealand-black-chromosome-1-is-associated-with-abnormal-dendritic-cell-function-leading-to-expansion-of-th1-th17-and-t-follicular-helper-tfh-cells/