Combined 4-1BB and CD28 costimulation could unleash lymphocytes from immunosuppression induced by adipose derived...

Adipose derived stem cells (ASCs) have the potential to differentiate into multiple cell lineages with the capacity to suppress immune cells. However, the exact mechanism of this suppression is not fully understood. We hypothesized that supplying additional lymphocyte costimulation through CD28 and 4-1BB could overturn the inhibitory effect of ASCs. To that end, PHA-activated human PBMCs were cocultured with ASCs or with conditioned media (CM) prepared from cultured ASCs. Growth was analyzed in the presence or absence of anti-CD28 and anti-4-1BB antibodies. Results from CFSE dilution analysis with flow cytometry showed that significant and dose-dependent suppression of PHA-activated lymphocytes occurred in the presence of ASC-like cells or ASC's CM. However, additional costimulation of T cells through CD28 and 4-1BB was able to fully recover lymphocyte proliferative capacity in the presence of ASC's CM. Neither of the costimulatory antibodies could fully recover lymphocyte proliferation following coculture with ASCs. Reversal of ASC's immunosuppression through costimulation suggests that further investigation of ASC suppression mechanisms is warranted, since many clinical applications of ASCs are based on this feature. Moreover, such findings have the potential to boost the usefulness of ASCs in the treatment of autoimmune disease.