Keratinocyte Growth Factor Improves Allogeneic Bone Marrow Engraftment through a CD4+Foxp3+ Regulatory T Cell-Dependent Mechanism

Abstract

Keratinocyte growth factor (KGF) protects mice from acute graft-vs-host disease and graft rejection by cytoprotective and yet incompletely understood immunological mechanisms. Recently, we showed that administration of KGF induces selective peripheral expansion of CD4+Foxp3+ regulatory T cells (Treg). In this study, we set out to assess whether the peripheral expansion of Treg accounts for the immunomodulatory effects of KGF after bone marrow (BM) transplantation. To exclude potentially confounding cytoprotective and thymopoietic effects of KGF, we applied KGF to congenic wild-type mice that served as T cell provider mice for T and B cell-deficient RAG-1−/− mice that were subsequently transplanted with allogeneic BM. Treatment of congenic T cell provider mice with KGF significantly improved engraftment and reduced graft rejection in BMT recipients. CD4+Foxp3+ Treg remained increased for 4 wk, while expansion of congenic CD3+ T cells was inhibited. To assess a causal relationship between expansion of Treg and improved BM engraftment, congenic Scurfy mice, which lack Foxp3+ Treg, served as T cell provider mice and were treated with KGF. KGF-treatment of Scurfy mice did not affect engraftment nor did it inhibit the expansion of congenic T cells. These data demonstrate that administration of KGF to the T cell provider mice improves engraftment of allogeneic BM through a CD4+Foxp3+ Treg-dependent mechanism.

Significant association of CD4+CD25+Foxp3+ regulatory T cells with clinical findings in patients with systemic lupus erythematosus

“…Even CD25 bright , which has been considered as a marker for identification of CD4 + Treg, may lead to confusing results in the cases of the tumor and autoimmune inflammatory diseases such as SLE because CD4 + Tregs defined by CD25 bright cannot be differentiated from activated effector T cells (20,21). Foxp3 has been proven to be a characteristic molecule related to the development and function of Treg (22,23). Foxp3 is also thought of as a relatively specific marker used in defining CD4 + Treg (6,11,24,25).…”

Thymic Rejuvenation: Are We There Yet?

“…As KGFR is expressed by several organs targeted by alloreactive T-cells, it was compelling to evaluate the effect of KGF in the setting of acute graft-versus-host disease (GVHD). In fact, current data have shown that KGF administration post-allogeneic BMT can: (i) facilitate alloengraftment [121], (ii) alleviate GVHD [122][123][124], (iii) protect epithelial cell in the gut mucosa while enhancing its repair [125], (iv) reduce the release of inflammatory cytokine [126], and (v) diminish allogeneic T-cell responses [121,127]. A subsequent study by Berent-Maoz et al further demonstrated that KGF not only protects TECs, but could also stimulate thymopoiesis indirectly by triggering them to secrete soluble factors [128].…”

Immunological Basis of Bone Marrow Failure after Allogeneic Hematopoietic Stem Cell Transplantation

“…In addition to IL-2, other molecules inducing in vivo expansion of Tregs display a potential to improve engraftment, including keratinocyte growth factor (KGF). KGF facilitated engraftment in an MHC-matched HSCT murine model by increasing the frequency of Tregs and enhancing their in vivo immunosuppression ability ( 56 ). Importantly KGF lost its ability to improve engraftment in Scurfy mice that lack Tregs.…”