The role of CD39-expressing regulatory T cells following treatment with alpha CD52: an effective therapeutic against central nervous system autoimmunity

Abstract Alemtuzumab (αCD52), a novel immunotherapy approved for the treatment of relapsing multiple sclerosis (MS), induces the widescale deletion of lymphocytes, including self-reactive T cells. Using the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), we previously found that following reconstitution of the immune compartment, there was an increased frequency of CD39+Foxp3+ regulatory T cells (Tregs) in the spleen and gut-associated lymphoid tissues of αCD52-treated mice. We hypothesized that the CD39-expressing Tregs that emerge following lymphocyte reconstitution would be suppressive against central nervous system autoimmunity. However, when CD39+ Tregs were purified from αCD52-treated mice and adoptively transferred to naïve recipients, they were unable to reduce the severity of EAE disease. We next used Foxp3/GFP reporter mice treated with αCD52 to compare the suppressive capacity of CD39+Foxp3+ versus CD39+Foxp3− Treg subsets and found that CD39+Foxp3+ Tregs, but not CD39+Foxp3− Tregs, were able to significantly reduce the proliferation of activated naïve T cells in vitro. Finally, we sought to determine if expression of CD39 was required for the therapeutic effects of αCD52 in the EAE model. Preliminary studies using a limited number of CD39 KO mice indicated that treatment with αCD52 was equally effective in both control and KO mice. Thus, our studies have identified potential differences in individual subsets of Tregs emerging after αCD52 treatment and suggest that expression of CD39 is dispensable for the short-term effectiveness of αCD52 in mice. Future studies are required to determine if CD39 expression on Tregs contributes to the long-term suppression of MS disease in patients treated with αCD52.