Background/Purpose: Stem cell-based regenerative medicine is a promising approach in tissue reconstruction. Mesenchymal stem cells (MSC) show therapeutic effects on human autoimmune diseases including systemic lupus erythematosus (SLE), but the underlying mechanisms remain largely unknown.

Methods:

The effects on inhibiting T cell proliferation by allogenic umbilical cord derived MSC were determined. Then MSC functional molecules were examined by real-time PCR under the stimulation of peripheral blood mononuclear cells (PBMC) from healthy controls and SLE patients, respectively. CD4+ and CD8+T cell were purified by microbeads to stimulate MSC, respectively, to determine IDO expression as well as supernatant cytokines, to further get to know which cell subset(s) or which molecule(s) involved in MSC mediated T cell proliferation inhibition. Meanwhile, the possible signaling pathways were assessed. Moreover, we analyzed the correlation between baseline serum cytokines and clinical response of MSC transplantation (MSCT).

Results: UC MSC efficiently inhibited T cell proliferation in both healthy controls and lupus patients, with a more inhibitory effect in lupus T cell. In vitro activated lupus PBMC significantly induced MSC to secret TGF-β1, IDO, HGF and IL-6, with a more than 200-fold increase of IDO. The addition of IDO inhibitor could almost completely abrogate MSC mediated T cell proliferation inhibition. Moreover, we found that lupus peripheral CD8+T cell markedly stimulated MSC to secret IDO and supernatant IFN-γ significant increased. The addition of anti-IFN-γ monoclonal antibody could inhibit IDO activity and similarly abrogate inhibition of T cell proliferation by MSC. We further found that lupus CD8+T cell secreted predominant intracellular IFN-γ compared to CD4+T cell or compared to healthy CD8+ or CD4+T cell subsets. Furthermore, in the presence of lupus CD8+T cell, IFNGR/JAK/STATs signaling pathways were activated, then to induce MSC to secret IDO and upregulate IDO activity. However, bone marrow MSC from lupus patients are less response to allogenic CD8+T cell or recombinant IFN-γ stimulation and produce far less IDO, consequently fail to efficiently inhibit T cell proliferation. In the last, clinical analysis showed that lupus patients had significant higher proportion and absolute number of CD3+CD4-CD8+T cell than healthy controls, and serum IFN-γ markedly increased. Predominant IFN-γ in lupus patients was mainly secreted by CD8+T cell. Baseline serum IFN-γ as well as CD8+T cell levels were significant higher in good responders than in poor responders who underwent UC MSC transplantation.

Conclusion: We uncovered a previously unrecognized CD8+T cell-IFN-γ-IDO axis that mediates the immunotherapy by allogenic MSC in lupus patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-cd8-t-cell-ifn-%ce%b3-ido-axis-is-required-for-mesenchymal-stem-cell-suppression-of-human-sle/