Distinct effects of IL-18 on the engraftment and function of human effector CD8 T cells and regulatory T cells.
IL-18 has pleotropic effects on the activation of T cells during antigen presentation. We investigated the effects of human IL-18 on the engraftment and function of human T cell subsets in xenograft mouse models. IL-18 enhanced the engraftment of human CD8(+) effector T cells and promoted the development of xenogeneic graft versus host disease (GVHD). In marked contrast, IL-18 had reciprocal effects on the engraftment of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in the xenografted mice. Adoptive transfer experiments indicated that IL-18 prevented the suppressive effects of Tregs on the development of xenogeneic GVHD. The IL-18 results were robust as they were observed in two different mouse strains. In addition, the effects of IL-18 were systemic as IL-18 promoted engraftment and persistence of human effector T cells and decreased Tregs in peripheral blood, peritoneal cavity, spleen and liver. In vitro experiments indicated that the expression of the IL-18Ralpha was induced on both CD4 and CD8 effector T cells and Tregs, and that the duration of expression was less sustained on Tregs. These preclinical data suggest that human IL-18 may have use as an adjuvant for immune reconstitution after cytotoxic therapies, and to augment adoptive immunotherapy, donor leukocyte infusions, and vaccine strategies.
Carroll
Richard G
RG
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Carpenito
Carmine
C
Shan
Xiaochuan
X
Danet-Desnoyers
Gwenn
G
Liu
Ronghua
R
Jiang
Shuguang
S
Albelda
Steven M
SM
Golovina
Tatiana
T
Coukos
George
G
Riley
James L
JL
Jonak
Zdenka L
ZL
June
Carl H
CH
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000378:metabolism; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008954:Models, Biological; D009368:Neoplasm Transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
D020382:Interleukin-18