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James L Funderburgh, Martha L Funderburgh, Mary M Mann, Yiqin Du, Kyle C McKenna, Andrew Hertsenberg; Stem cells from corneal stroma suppress T-cell activation via cell-cell interactions. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2073.
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© ARVO (1962-2015); The Authors (2016-present)
Human corneal stromal stem cells introduced into mouse corneal stroma, remain viable for extended time periods, restoring transparency to corneas of lumican null mice and to wounded corneas of normal mice without immune rejection. Mesenchymal stem cells are also reported to suppress corneal allograft rejection. Primary human fibroblasts in mouse corneas, however, elicit a strong T-cell response demonstrating the specialied immune-modulatory property of stem cells. This study examined the mechanism by which human corneal stromal stem cells (hCSSC) block activation of T-cells, mediators of tissue rejection.
Splenocytes from OT-1 mice were activated by mouse peritoneal macrophages primed with ovalbumin peptides. Human peripheral blood mononuclear cells (PBMCs) labeled with CFSE were activated with concanavalin A (ConA) or with anti-CD3/CD28 beads in vitro for four days in the presence of hCSSC. Proliferation and expression of activated T-cell markers were examined by flow cytometry.
T-cells from OT-1 mice responded to ovalbumin-primed antigen-presenting cells by proliferation and by expression of CD25 and CD69 antigens. The presence of hCSSC at a 1:100 ratio of hCSSC:splenocytes significantly reduced activation and 1:5 ratio eliminated activation. CD3 T-cells in PBMCs, activated with ConA or anti-CD3/CD28 divided up to 5 times in 4 days. PBMC:hCSSC at a ratio of 1:6 fully blocked this proliferation. Suppression of T-cell activation was enhanced by activation of hCSSC with IFN-gamma and TNF-alpha. Physical separation of hCSSC from PBMCs in transwells eliminated the ability to block T-cell activation. Results acheived statistical significance (p<0.05) as determined by t-test.
Our data support the idea that T-cell activation can be blocked by corneal stromal stem cells by direct cell-cell contact, possibly via interaction of the PD-L1 (CD274) cell-surface protein. This suppression mechanism appears to be distinct from the suppression of neutrophil activation mediated by stem cell secretion of TSG6. Adult corneal stomal stem cells, therefore appear to manage immune response in their environment via multiple mechanisms.
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