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CTLA4-Ig Preserves Thymus-Derived T Regulatory Cells

Background CTLA-4 immunoglobulin fusion proteins (CTLA4-Ig) suppress immune reactions by blocking the T-cell costimulatory CD28–CD80-86 pathway and are used in clinical trials for diseases featuring exaggerated T-cell reactivity including autoimmune diseases and allograft rejection. However, because CTLA4-Ig has been suspected to interfere with T regulatory (Treg) cell homeostasis and function, recently, substantial concerns on CTLA4-Ig’s potentially antitolerogenic effects have been raised. Methods We tested immunoregulatory CTLA4-Ig explicitly for its effect on Treg cell numbers, frequencies and function in an in vitro murine major histocompatibility complex mismatched setting using C57BL/6 bone marrow–derived dendritic cells as stimulators of allogeneic Balb/c Foxp3gfp+ T cells, which allowed for tracing Treg cells in a straightforward fashion. Results The presence of CTLA4-Ig in mixed leukocyte reactions—while dampening the global proliferative response of allostimulated Balb/c T cells—resulted in a relative increase of the frequency of thymus-derived CD4+CD25+Foxp3+ Treg cells with intact suppressive activity. This relative increase was caused by a selective inhibitory effect of CTLA4-Ig on proliferating conventional T cells, whereas the proliferative capacity of Treg cells in cell cultures remained unaffected. Additionally, in the presence of CTLA4-Ig, the frequency of apoptosis was decreased in these cells. Conclusion Our findings unequivocally demonstrate that CTLA4-Ig does not negatively affect Treg cell frequencies and function in vitro.