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Abstract Number: 112

Impact of Interleukin-9 on the Immune Suppressive Functions of Regulatory T Cells in Rheumatoid Arthritis

Sushmita Chakraborty 1, Ranjan Gupta 2, Rinkee Kumari 1 and Dipendra Kumar Mitra1, 1All India Institute of Medical Sciences, Delhi, Delhi, India, 2All India Institute of Medical Sciences, New Delhi, India

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Immune Dysregulation and Synovial Immune Biology, interleukins (IL), Rheumatoid arthritis (RA), T-Regulatory Cells

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Session Information

Date: Sunday, November 10, 2019

Session Title: T Cell Biology & Targets in Autoimmune & Inflammatory Disease Poster

Session Type: Poster Session (Sunday)

Session Time: 9:00AM-11:00AM

Background/Purpose: An important component of the immune tolerance is regulatory T cells (Tregs), which prevents autoimmunity and restrains inflammatory reactions. In Rheumatoid Arthritis (RA), there is a consensus among researchers that Tregs are enriched in the synovial fluid (SF) of individuals with RA. However, despite their synovial accumulation, the synovial inflammation continues in RA suggesting their inability to mediate suppression in the pathogenic site. Recently, our group has shown the enrichment of interleukin-9 (IL-9) producing helper T (Th9) cells in synovial fluid and its positive correlation with disease activity. Therefore, in this study we investigated whether IL-9 plays any role in dysfunctioning of synovial Tregs in RA.

Methods: Mononuclear cells were isolated from peripheral blood (PB) and synovial fluid (SF) of patients with active RA. In vitro stimulation of mononuclear cells was performed by engagement of anti-CD3 and anti-CD28 monoclonal antibodies. We performed IL-9 pathway blocking using a blocking antibody against IL-9 receptor alpha chain. Polychromatic flowcytometry was performed to evaluate the frequencies of IL-10, TGF-β, PD-1 and CTLA-4 positive Tregs (CD4+, CD25+ and FOXP3+).

Results: Treg cells mediate their suppressive function by various ways like contact dependent involving immune inhibitory molecules like programmed cell death protein 1 (PD-1) and contact independent involving suppressive cytokines like IL-10 and TGF-β.We observed that the frequency of CD4+ FoxP3+T cells was significantly higher in the Synovial Fluid (SF) compared to that of Peripheral Blood (PB) from patients. However, Tregs derived from SF are functionally impaired and thus fail to suppress the inflammation at the local site. We observed that in vitro stimulation of synovial T cells in presence of IL-9 receptor alpha chain blocking antibody, enhanced the frequency of IL-10 and TGF beta producing Tregs. Also, IL-9 blocking resulted in increase in frequency of PD-1 and CTLA4 expressing Tregs. These observations indicated that IL-9/IL-9 receptor pathway inhibits the suppressive function of synovial fluid derived Tregs. We next checked the effect of recombinant IL-9 on peripheral blood derived Tregs from healthy individuals. We observed that in vitro stimulation of mononuclear cells in presence of recombinant IL-9 results in reduced frequency of IL-10 and TGF beta producing Tregs, suggesting that IL-9 has negative impact on Tregs.

Conclusion: Our results indicate that IL-9 pathway blocking in RA may contribute in the resolution of inflammation by restoring the Treg function essential for immune tolerance.

Figure 1: Representative and Cumulative Plots showing Treg frequency in PB and SF of RA patients. Lymphocytes were gated by Forward scatter -FSC- vs. Side Scatter -SSC-. Representative dot plots showing CD4+Foxp3+ Tregs in PB -Figure 1A; left panel- and SF -Figure 1A; Right panel- RA patients. Cumulative plots showing frequency of CD4+Foxp3+ cells in PB vs SF in RA patients -Figure 1B; p<0.05 is significant-. SFMC and PBMC were stimulated . Cumulative plots showing frequency of CD4+Foxp3+IL-10+ cells and CD4+Foxp3+TGFβ+ cells in PB vs SF in RA patients -Figure 1C & D-.

Figure 3: Effect of in vitro blocking IL-9 receptor -IL-9R- on frequency of TGF β and IL10 producing Tregs. Synovial fluid derived mononuclear cells -SMNCs- were stimulated in presence or absence of monoclonal antibody binding to IL-9 receptor alpha . Lymphocytes were gated by Forward scatter -FSC- vs. Side Scatter -SSC-.On gated CD4+, the frequency of TGF-β and IL-10 producing Foxp3+ cells were assessed. Cumulative Plots showing frequency of CD4+FOXP3+TGFβ+ -A- and CD4+FOXP3+IL10+-B-.

Figure 3. Peripheral blood mononuclear cells -PBMCs- of RA patient were stimulated in presence or absence of recombinant IL-9. On gated CD4+ CD25+ cells, the frequency of TGF-β -A- and IL-10 -B- producing Foxp3+ cells were assessed using Flow cytometry.


Disclosure: S. Chakraborty, None; R. Gupta, None; R. Kumari, None; D. Mitra, None.

To cite this abstract in AMA style:

Chakraborty S, Gupta R, Kumari R, Mitra D. Impact of Interleukin-9 on the Immune Suppressive Functions of Regulatory T Cells in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/impact-of-interleukin-9-on-the-immune-suppressive-functions-of-regulatory-t-cells-in-rheumatoid-arthritis/. Accessed May 26, 2022.
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