Inhibition of calcineurin abrogates while inhibition of mTOR promotes regulatory T cell expansion and graft-versus-host disease protection by IL-2 in allogeneic bone marrow transplantation.

Abstract

Regulatory T cells (Treg)s attenuate excessive immune responses, making their expansion beneficial in immune-mediated diseases including allogeneic bone marrow transplantation (BMT)-associated graft-versus-host disease (GVHD). We have recently reported that Treg expansion does not require phospholipase Cγ activation when IL-2 is provided. As such, the combination of IL-2 and a calcineurin inhibitor (Cyclosporine A; CsA) expands Tregs while inhibiting Tconv proliferation and protects against a mouse model of multiple sclerosis. However, CsA inhibits Treg proliferation in the presence of a TCR stimulus, suggesting that CsA may negatively impact Treg proliferation when they receive strong allogeneic MHC-mediated TCR signals. In this study, we show that CsA inhibits Treg proliferation and inducible Treg generation in allogeneic but not in syngeneic BMT when IL-2 is provided. In contrast to CsA, the mTOR inhibitor (Rapamycin) almost completely suppressed IL-2-mediated Treg proliferation. However, CsA and Rapamycin inhibited Treg proliferation to a similar extent when TCR stimulation was provided. Furthermore, Rapamycin promoted Treg expansion and inducible Treg generation in allogeneic BMT recipients treated with IL-2. Consistent with these observations, CsA abrogated while Rapamycin promoted the protective effect of IL-2 on allogeneic BMT-induced GVHD. These results suggest that while CsA permits IL-2-induced Treg proliferation in the syngeneic setting (absence of strong TCR signals), CsA in combination with IL-2 may be detrimental for Treg proliferation in an allogeneic setting. Thus, in allogeneic settings, an mTOR inhibitor such as Rapamycin is a better choice for adjunct therapy with IL-2 in expansion of Tregs and protection against allogeneic BMT-induced GVHD.

• Authors: Atsushi Satake, Amanda M Schmidt, Shosaku Nomura, Taku Kambayashi
• Journal: PloS one (PLoS One) Vol. 9 Issue 3 Pg. e92888 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24658577 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Calcineurin Inhibitors
• Immunosuppressive Agents
• Interleukin-2
• Receptors, Antigen, T-Cell
• Cyclosporine
• TOR Serine-Threonine Kinases
• Calcineurin

Topics

• Animals
• Bone Marrow Transplantation (adverse effects)
• Calcineurin (metabolism)
• Calcineurin Inhibitors
• Cyclosporine (pharmacology)
• Graft vs Host Disease (immunology, metabolism, prevention & control)
• Immunosuppressive Agents (pharmacology)
• Interleukin-2 (pharmacology)
• Lymphocyte Activation (drug effects, immunology)
• Melanoma, Experimental
• Mice
• Receptors, Antigen, T-Cell (metabolism)
• T-Lymphocytes, Regulatory (drug effects, immunology, metabolism)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Tissue Donors
• Transplantation, Homologous