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

Abstract

Although CD4 ؉ CD25 ؉ T cells (T regulatory cells [Tregs]) and natural killer T cells (NKT cells) each protect against graftversus-host disease (GVHD), interactionsbetween these 2 regulatory cell populations after allogeneic bone marrow transplantation (BMT) have not been studied. We show that host NKT cells can induce an in vivo expansion of donor Tregs that prevents lethal GVHD in mice after conditioning with fractionated lymphoid irradiation (TLI) and anti-T-cell antibodies, a regimen that models human GVHDprotective nonmyeloablative protocols using TLI and antithymocyte globulin (ATG), followed by allogeneic hematopoietic cell transplantation (HCT). GVHD protection was lost in NKT-cell-deficient J␣18 ؊/؊ hosts and interleukin-4 (IL-4) ؊ IntroductionGraft-versus-host disease (GVHD), a major complication of allogeneic bone marrow transplantation, causes injury to the host intestines, skin, and liver, [1][2][3][4] and is mediated by donor conventional CD4 ϩ and CD8 ϩ T cells. 2,5 Both natural killer T cells (NKT cells) 6-8 and CD4 ϩ CD25 ϩ T regulatory cells (Tregs) 9-11 can regulate GVHD without prior exposure to the target antigens. [6][7][8][9][10][11][12][13][14][15][16] Host NKT cells express an invariant V␣14J␣18 T-cell receptor (TCR)␣ chain, and secrete large amounts of interleukin (IL)-4 and/or interferon (IFN)-␥ within hours after activation via TCR recognition of the nonpolymorphic CD1d antigen-presenting molecule. 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 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. 35,36 We investigated whether host NKT cells can interact synergistically with donor Tregs to protect against GVHD after bone marrow transplantation. Hosts were conditioned with total lymphoid irradiation (TLI) and antithymocyte serum (ATS), a regimen that protects mice against lethal GVHD that has been successfully applied to hematopoietic cell transplantation in humans to achieve a low incidence of acute GVHD. 37,38 Our results demonstrate the novel finding that host NKT cells and donor Tregs interact to prevent conventional donor T cells from expanding and inducing lethal GVHD. Proliferation of donor Tregs in vivo occurred after transplantation and was dependent on host NKT cell secretion of IL-4. Methods MiceWild-type (BALB/cJ and BALB/cByJ) and IL-4 Ϫ/Ϫ male BALB/c (H-2 d ) male mice, 8 to 10 weeks old, were obtained from The Jackson Laboratory (Bar Harbor, ME) and the Department of Com...

New perspectives on the biology of acute GVHD

“…[52][53][54] (3) Host NKT cells can negatively regulate APC interactions with donor T cells in an IL-4-and Th2-dependent manner. 55,56 In contrast, donor NKT cells activate this response. 45,57,58 (4) B cells: the role of B cells in acute GVHD is currently under investigation, particularly regarding the possible role in attenuating the disease.…”

Reduced levels of both circulating CD4+CD25+CD127low/neg and CD4+CD8neg invariant natural killer regulatory T cells in stable heart transplant recipients

“…iNK T cells modulate the Treg functions quantitatively and qualitatively through IL-2, IL-4 and IL-10-dependent mechanisms, whereas Treg can suppress the proliferation, cytokine release and cytotoxic activity of iNK T cells by cell contactdependent mechanisms [13,14]. The existence of an IL-10 and IL-4-dependent immune regulatory interplay among iNK T cells, dendritic cells and CD4 Treg has been shown in animal models of allogenic cardiac and bone marrow transplantation, demonstrating the importance of this crossregulation in allograft tolerance induction [15,16]. Both these regulatory subsets of T cells could therefore act in the control of allograft rejection, in a regulatory network of cytokine production and cell-cell interactions in situ.…”

“…In humans, 'classical' type I iNK T co-express the invariant TCR Va24-Ja18 and Vb11 chains [11], and these cells have been shown to be required in the induction of long-term allograft tolerance [12]. Several recent reports have described a cross-regulation between Treg and iNK T [13,14], both subsets therefore having been shown to be important for allograft tolerance induction [15,16], possibly in a co-ordinated fashion.…”

Risks and benefits of sex-mismatched hematopoietic cell transplantation differ according to conditioning strategy

“…24,25 These regulatory T cells are thought to have a potential not only to suppress fatal acute GVHD but also to preserve the antitumor effect of cytotoxic T cells. 26,27 Future studies of alloreactive cell populations could help to clarify the immune dynamics that account for the GVL benefit by sex-mismatched HCT in TLI-ATG patients.…”