Allogeneic cord blood regulatory T cells can resolve lung inflammation

Abstract

Background aims: CD4⁺CD25⁺CD127^lo regulatory T cells (Tregs) are responsible for maintaining immune homeostasis. Tregs can be rendered defective and deficient as a result of the immune imbalance seen in lung injury, and such dysfunction can play a major role in continued tissue inflammation. The authors hypothesized that adoptive therapy with healthy allogeneic umbilical cord blood (UCB)-derived Tregs may be able to resolve inflammation.

Results: Ex vivo-expanded UCB Tregs exhibited a unique phenotype with co-expression of CD45RA⁺CD45RO⁺ >80% and lung homing markers, including CD49d. UCB Tregs did not turn pathogenic when exposed to IL-6. Co-culture with increasing doses of dexamethasone led to a synergistic increase in UCB Treg-induced apoptosis of conventional T cells (Tcons), which translated into significantly higher suppression of proliferating Tcons, especially at a lower Treg:Tcon ratio. Multiple injections of UCB Tregs led to their preferential accumulation in lung tissue in an immune injury xenogenic model. A significant decrease in lung resident cytotoxic CD8⁺ T cells (P = 0.0218) correlated with a sustained decrease in their systemic distribution compared with controls (P < 0.0001) (n = 7 per arm) as well as a decrease in circulating human soluble CD40 ligand level (P = 0.031). Tissue architecture was preserved in the treatment arm, and a significant decrease in CD3⁺ and CD8⁺ burden was evident in immunohistochemistry analysis.

Conclusions: UCB Treg adoptive therapy is a promising therapeutic strategy for treatment of lung injury.

Keywords: adoptive cell therapy; cord blood; lung inflammation; lung injury; regulatory T cells.