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Natural killer cells and regulatory T cells: how to manipulate a graft for optimal GVL.

ABSTRACT: Two of the major complications that limit the efficacy of allogeneic hematopoietic cell transplantation (allo-HCT) are disease relapse and GVHD. Due to their rapid recovery early after allo-HCT and their ability to kill malignant targets without prior exposure, natural killer (NK) cells have been considered one of the main effector cells that mediate early GVL reactions. Conversely, regulatory T ells (Tregs) have proven to be critical in facilitating self-tolerance. Both murine and human studies have demonstrated a significant role for Tregs in the modulation of GVHD after allo-HCT. This article reviews the mechanisms of how these 2 cell types carry out these functions, focusing on the post-allo-HCT period. Surprisingly, relatively few studies have addressed how Tregs and NK cells interact with one another and whether these interactions are antagonistic. Although preclinical studies suggest active cross-talk between NK cells and Tregs, early clinical studies have not shown a detrimental impact of Treg therapy on relapse. Despite this, interruption of tolerogenic signals may enhance the efficacy of NK effector functions. Methods to transiently impair Treg functions and augment NK cell alloreactivity will be discussed.

SUBMITTER: Verneris MR

PROVIDER: S-EPMC4020013 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Natural killer cells and regulatory T cells: how to manipulate a graft for optimal GVL.

Verneris Michael R MR

Hematology. American Society of Hematology. Education Program 20130101

Two of the major complications that limit the efficacy of allogeneic hematopoietic cell transplantation (allo-HCT) are disease relapse and GVHD. Due to their rapid recovery early after allo-HCT and their ability to kill malignant targets without prior exposure, natural killer (NK) cells have been considered one of the main effector cells that mediate early GVL reactions. Conversely, regulatory T ells (Tregs) have proven to be critical in facilitating self-tolerance. Both murine and human studies ...[more]

PMID: 24319201

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Project description:BackgroundCytomegalovirus establishes lifelong persistency in the host and leads to life threatening situations in immunocompromised patients. FoxP3+ T regulatory cells (Tregs) critically control and suppress innate and adaptive immune responses. However, their specific role during MCMV infection, especially pertaining to their interaction with NK cells, remains incompletely defined.MethodsTo understand the contribution of Tregs on NK cell function during acute MCMV infection, we infected Treg depleted and undepleted DEREG mice with WT MCMV and examined Treg and NK cell frequency, number, activation and effector function in vivo.ResultsOur results reveal an increased frequency of activated Tregs within the CD4+ T cell population shortly after MCMV infection. Specific depletion of Tregs in DEREG mice under homeostatic conditions leads to an increase in NK cell number as well as to a higher activation status of these cells as compared with non-depleted controls. Interestingly, upon infection this effect on NK cells is completely neutralized in terms of cell frequency, CD69 expression and functionality with respect to IFN-? production. Furthermore, composition of the NK cell population with regard to Ly49H expression remains unchanged. In contrast, absence of Tregs still boosts the general T cell response upon infection to a level comparable to the enhanced activation seen in uninfected mice. CD4+ T cells especially benefit from Treg depletion exhibiting a two-fold increase of CD69+ cells 40 h and IFN-?+ cells 7 days p.i. while, MCMV infection per se induces robust CD8+ T cell activation which is also further augmented in Treg-depleted mice. Nevertheless, the viral burden in the liver and spleen remain unaltered upon Treg ablation during the course of infection.ConclusionsThus, MCMV infection abolishes Treg suppressing effects on NK cells whereas T cells benefit from their absence during acute infection. This study provides novel information in understanding the collaborative interaction between NK cells and Tregs during a viral infection and provides further knowledge that could be adopted in therapeutic setups to improve current treatment of organ transplant patients where modulation of Tregs is envisioned as a strategy to overcome transplant rejection.

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Natural killer cells and regulatory T cells: how to manipulate a graft for optimal GVL.

Publications

Natural killer cells and regulatory T cells: how to manipulate a graft for optimal GVL.

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