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. 2024 Feb 1;8(2):172-181.
doi: 10.4049/immunohorizons.2300023.

TCDD and CH223191 Alter T Cell Balance but Fail to Induce Anti-Inflammatory Response in Adult Lupus Mice

Fernando Gutierrez  1 , Quiyana M Murphy  2 , Brianna K Swartwout  3 , Kaitlin A Read  1 , Michael R Edwards  1 , Leila Abdelhamid  1 , Xavier Cabana-Puig  1 , James C Testerman  1 , Tian Xu  1 , Ran Lu  1 , Pavly Amin  1 , Thomas E Cecere  1 , Christopher M Reilly  4 , Kenneth J Oestreich  5 , Stanca M Ciupe  2 , Xin M Luo  1
Affiliations

TCDD and CH223191 Alter T Cell Balance but Fail to Induce Anti-Inflammatory Response in Adult Lupus Mice

Fernando Gutierrez et al. Immunohorizons. .

Abstract

Aryl hydrocarbon receptor (AhR) responds to endogenous and exogenous ligands as a cytosolic receptor, transcription factor, and E3 ubiquitin ligase. Several studies support an anti-inflammatory effect of AhR activation. However, exposure to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early stages of development results in an autoimmune phenotype and exacerbates lupus. The effects of TCDD on lupus in adults with pre-existing autoimmunity have not been described. We present novel evidence that AhR stimulation by TCDD alters T cell responses but fails to impact lupus-like disease using an adult mouse model. Interestingly, AhR antagonist CH223191 also changed T cell balance in our model. We next developed a conceptual framework for identifying cellular and molecular factors that contribute to physiological outcomes in lupus and created models that describe cytokine dynamics that were fed into a system of differential equations to predict the kinetics of T follicular helper (Tfh) and regulatory T (Treg) cell populations. The model predicted that Tfh cells expanded to larger values following TCDD exposure compared with vehicle and CH223191. Following the initial elevation, both Tfh and Treg cell populations continuously decayed over time. A function based on the ratio of predicted Treg/Tfh cells showed that Treg cells exceed Tfh cells in all groups, with TCDD and CH223191 showing lower Treg/Tfh cell ratios than the vehicle and that the ratio is relatively constant over time. We conclude that AhR ligands did not induce an anti-inflammatory response to attenuate autoimmunity in adult lupus mice. This study challenges the dogma that TCDD supports an immunosuppressive phenotype.

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Conflict of interest statement

The authors have no financial conflicts of interest.

Figures

FIGURE 1.
FIGURE 1.
TCDD and CH223191 do not significantly alter TGF-β or impact lupus-like disease in the MRL/lpr mouse model. (A) MRL/lpr mice received vehicle, 10 µg/kg TCDD, or 10 mg/kg CH233191 according to the diagram of experimental design. The same experiment was repeated once, with n = 8–9/group in each experiment. (B) Serum TGF-β at T0, T2, and T7. (C) T7 splenic Tgfb1 transcript level. (D) T7 spleen weight. (E) Level of anti-dsDNA IgG autoantibodies at T0, T2, and T7. (F) T7 splenic Il22 transcript level. *p < 0.05 by one-way ANOVA. (G) Proteinuria from 8 to 14 wk of age. **p < 0.01 by two-way ANOVA. (H) Weights of superficial (axillary and cervical) lymph nodes at T7. Only one cage per group (n = 5/group) was analyzed for this parameter. *p < 0.05 based on one-way ANOVA. For (D), (E), and (G), data from both experiments were combined.
FIGURE 2.
FIGURE 2.
TCDD and CH223191 alter serum ANA patterns on HEp-2 cells. (A) Representative images. (B) Pie charts showing the proportions of different ANA patterns. The peripheral pattern is indicative of acute SLE-like disease. The homogeneous pattern is the most typical of SLE. Both peripheral and homogeneous patterns indicate autoantibodies against dsDNA and histones. The speckled pattern, which is rare in SLE, usually indicates autoantibodies against mitochondria. The cytoplasmic spider webs suggest autoantibodies against structural Ags such as actin and myosin.
FIGURE 3.
FIGURE 3.
TCDD and CH223191 impact Tfh and Treg cells, respectively. (A) Representative FACS plots and percentage of Tfh cells within CD4+ T cells in the T7 spleen. **p < 0.01 by one-way ANOVA. FMO, fluorescence minus one. (B) Representative FACS plots and percentage of Treg cells within CD4+ T cells in the T7 spleen. **p < 0.01 by one-way ANOVA. (C) Ratio of Treg to Tfh cells in the T7 spleen. *p < 0.05 by one-way ANOVA. Data from one representative experiment are shown (n = 8/group).
FIGURE 4.
FIGURE 4.
Predicted population dynamics over time versus data. Theoretical curves (black lines) obtained by fitting solutions of the form w(t) = aebt for populations w = {A, I6, Fβ} and of the form w(t) = xt2 + yt + z for populations w = {I2, I12} to time series data for experimental groups. (A) Vehicle (blue points). (B) TCDD (green points). (C) CH223191 (red points). Parameters estimates are listed in Supplemental Tables I and II. The x-axis represents weeks postinjection with T0, T2, and T7 representing 8, 10, and 15 wk since birth, respectively. For the Ab populations (anti-dsDNA) the y-axis represents the averaged normalized absorbance. For cytokine populations, the y-axis represents the average (pg/ml).
FIGURE 5.
FIGURE 5.
Dynamics of Tfh and Treg population over time. (A) Model diagram of cytokine interactions with Tfh and Treg cell populations. (B) Logarithmic dynamics of percentage of Tfh (top) and Treg (bottom) cells within CD4+ T cells from T0 to T7 obtained by evaluating model (Eq. 1C). Parameters are given in Supplemental Table III. (C) Logarithmic dynamics of Treg/Tfh cell ratio given by evaluating model (Eq. 1C) from T0 to T7. Dotted lines correspond to Tr/Tfh = 1. Parameters are given in Supplemental Table III.
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References

    1. Lamas, B., Natividad J. M., Sokol H.. 2018. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol. 11: 1024–1038. - PubMed
    1. Von Burg, R. 1988. TCDD. J. Appl. Toxicol. 8: 145–148. - PubMed
    1. Tonn, T., Esser C., Schneider E. M., Steinmann-Steiner-Haldenstätt W., Gleichmann E.. 1996. Persistence of decreased T-helper cell function in industrial workers 20 years after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Environ. Health Perspect. 104: 422–426. - PMC - PubMed
    1. Saberi Hosnijeh, F., Portengen L., Bueno-de-Mesquita H. B., Heederik D., Vermeulen R.. 2013. Circulating soluble CD27 and CD30 in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Cancer Epidemiol. Biomarkers Prev. 22: 2420–2424. - PubMed
    1. Singh, N. P., Singh U. P., Singh B., Price R. L., Nagarkatti M., Nagarkatti P. S.. 2011. Activation of aryl hydrocarbon receptor (AhR) leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis. PLoS One. 6: e23522. - PMC - PubMed

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