Total lymphoid irradiation nonmyeloablative preconditioning enriches for IL-4–producing CD4+-TNK cells and skews differentiation of immunocompetent donor CD4+cells

Abstract

Preconditioning with the nonmyeloablative regimen total lymphoid irradiation (TLI) before hematopoietic cell transplantation facilitates the establishment of mixed chimerism and protects against graft-versus-host disease. We reported that the development of mixed chimerism requires interleukin (

Host natural killer T cells induce an interleukin-4–dependent expansion of donor CD4+CD25+Foxp3+ T regulatory cells that protects against graft-versus-host disease

“…35,36 NKT cells from irradiated mice develop a Th2 bias via unknown direct or indirect mechanisms, with increased IL-4 secretion after activation. 12,13,23 Reports suggest that IL-4-biased NKT cells may be resistant to apoptosis, 49 which could confer a survival advantage to these host cells after sublethal host-conditioning strategies. These findings may account for the importance of IL-4 in our system, where NKT cells predominate among host T cells after TLI.…”

“…It has been shown that TLI and anti-thymocyte antibody conditioning can induce a potent Th2 polarization of donor CD4 ϩ T cells, [23][24] and that Th2 polarization of conventional donor T cells can contribute to GVHD protection in conventional TBI transplant models. [25][26] To examine this possibility, we compared the day 6 accumulation of donor CD8 ϩ T cell GVHD effectors in wild-type BALB/c hosts given CD4 Ϫ/Ϫ donor spleen and marrow cells with and without purified wild-type donor splenic Tregs in our TLI/ATS model.…”

“…13,[17][18][19][20][21] Host or donor NKT cell-mediated GVHD protection has been reported to be dependent on NKT cell secretion of cytokines, which induce T helper (Th) 2 polarization of conventional T cells, 8,22 and thereby attenuate their capacity to induce GVHD. 8,12,13,[23][24][25][26][27] Naturally occurring CD4 ϩ CD25 ϩ Tregs of either host or donor origin can protect against GVHD by suppressing the function of donor conventional T cells through direct cell contact [28][29][30][31][32][33] or secretion of cytokines, including IL-10. 9,32,34 In nontransplant settings, activation of NKT cells using ␣-galactosyl ceramide, a marine sponge-derived glycolipid, can activate Tregs via NKT-cell secretion of IL-2.…”

Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

“…Irradiation and/or chemotherapy leads to activation of host cells, resulting in the release of proinflammatory cytokines, such as TNF-α, IL-1 and IL-4 [71][72][73][74], and upregulation of co-stimulatory molecules, such as CD80 [75]. In a recent study, activation markers I-A b (class II) and CD86 were upregulated on splenic DCs as early as 6 h after TBI.…”

Novel treatment concepts for graft-versus-host disease

“…[102][103][104] This effect primarily depends on NKT-cell secreted IL-4, which is known to drive TH2-polarization of conventional donor-derived T cells, 105,106 attenuating their capacity to mediate GVHD. 105,107,108 Thus, NKT cells expressing IL-4 can be referred to as another regulatory lymphocyte population. Activation of host NKT cells appears to be crucial for GVHD prevention, as transplantation of CD1 days-and J␣-18-deficient host mice with wild-type transplants allowed graft versus leukemia reaction but failed to prevent GVHD.…”