Prevention of Acute Graft-Versus-Host Disease by CD4+CD25+ Regulatory T Cells Is Dependent on the CD30/CD153 Pathway.

CD4⁺CD25⁺ regulatory T (Treg) cells suppress acute graft versus host disease (aGVHD), prevent autoimmunity and delay allograft rejection. CD30 and other TNF-R family members have been demonstrated to be expressed by Treg and to function as alternative costimulatory pathways for T cell activation. In this study we assessed the significance of the CD30/CD153 pathway in Tregs suppression of aGVHD in a murine major MHC mismatch BMT model. Using bioluminescence imaging proliferation of donor derived luciferase-labeled CD4⁺ and CD8⁺ T cells was quantified at serial time points after transplantation. Treg suppressed the early expansion of alloreactive T-cells. Immunofluorescence microscopy revealed a predominant infiltration of donor derived Treg in CD153 positive regions of secondary lymphoid organs, namely parafollicular T cell zones of lymph nodes and the subepithelial dome regions of Peyers Patches. In vivo blockade of the CD30/CD153 pathway with anti CD153 Ab did not alter Treg migration to secondary lymphoid organs but reduced their suppressive effect. Proliferation of donor T cells as measured in photons/second/mouse was significantly higher in animals receiving Treg and CD153 blocking antibodies as compared to recipients of Treg only (p=0.0038). Gene expression profiling of Treg with DNA microarrays indicated a Treg signature that was consistently found in different mouse strains. This Treg signature was altered after CD153 blockade in vitro. Importantly, aGVHD lethality was significantly increased (p=0.021) when CD30-CD153 interaction was blocked during Treg transfer. This study provides direct evidence that the TNF-R family member CD30 is critical for Treg cell function in the regulation of pathological T cell responses that lead to aGVHD.