Enhancement of natural killer (NK) cell cytotoxicity by fever-range thermal stress is dependent on NKG2D function and is associated with plasma membrane NKG2D clustering and increased expression of MICA on target cells

Abstract

Circulating NK cells normally experience temperature gradients as they move about the body, but the onset of inflammation can expose them and their targets to febrile temperatures for several hours. We found that exposure of human peripheral blood NK cells and target cells to fever-range temperatures significantly enhances lysis of Colo205 target cells. A similar effect was not observed when NK cell lines or IL-2-activated peripheral blood NK cells were used as effectors, indicating that thermal sensitivity of effectors is maturation or activation state-dependent. Use of blocking antibodies revealed that this effect is also dependent on the function of the activating receptor NKG2D and its ligand MHC class I-related chain A (MICA). On NK cells, it was observed that thermal exposure does not affect the total level of NKG2D surface expression, but does result in its distinct clustering, identical to that which occurs following IL-2-induced activation. On tumor target cells, a similar, mild temperature elevation results in transcriptional up-regulation of MICA in a manner that correlates with increased sensitivity to cytolysis. Overall, these data reveal that NK cells possess thermally responsive regulatory elements, which facilitate their ability to capitalize on reciprocal, stress-induced changes simultaneously occurring on target cells during inflammation and fever.

The influence of infection early after allogeneic stem cell transplantation on the risk of leukemic relapse and graft‐versus‐host disease

“…A recent experimental study has revealed that exposure of human peripheral blood NK cells and target cells to fever-range temperatures significantly enhances lysis of target cells and, for tumor target cells, mild temperature elevation results in transcriptional upregulation of the major histocompatibility complex class I-related chain (MICA) in a manner that correlates with increased sensitivity to cytolysis [5], which also supports the association between early post-transplant infection and the accentuated GVL effect noted in our study. There are several cytokines commonly associated with both the GVL effect and early post-transplant infection.…”

“…The GVL effect is mediated by a complex network of immune cells and cytokines [1][2][3]. As inflammatory events following allogeneic SCT can change the activity of the host and donor graft immune cells that release various inflammatory cytokines [4][5][6], post-transplant infection may influence the milieu of the GVL effect and, accordingly, the risk of posttransplant leukemic relapse.…”

“…The GVL effect is mediated by a complex network of immune cells and cytokines [1][2][3]. As inflammatory events following allogeneic SCT can change the activity of the host and donor graft immune cells that release various inflammatory cytokines [4][5][6], post-transplant infection may influence the milieu of the GVL effect and, accordingly, the risk of posttransplant leukemic relapse.Post-transplant infections usually occur early after transplantation and the activation of host antigen-presenting cells and donor NK cells has been shown to occur quite early in both experimental and human allogeneic SCT [7,8]. We investigated whether a febrile infection (FI) before posttransplant day 21 was associated with a risk of leukemic relapse and graft-versus-host disease (GVHD) in patients with acute leukemia.…”

Cancer immunity and therapy using hyperthermia with immunotherapy, radiotherapy, chemotherapy, and surgery

“…Activated NK cells have nonspecific anticancer potential by secreting cytotoxic molecules including perforin and granzyme [33] and death receptors such as FasL, TRAIL, and TNF-α . Additionally, heat stress can enhance the distinct clustering of NK cell-activating receptors such as NKG2D on the surface of NK cells and the expression of NK cell-activating ligands, including major histocompatibility complex class I-related chain A (MICA) [64,65] . Moreover, an increase in the expression of MICA and increased cytotoxicity of NK cells were also observed in several cancer cell lines [66] .…”

Improving efficacy of hyperthermia in oncology by exploiting biological mechanisms

“…Hyperthermia not only alters expression of vascular adhesion molecules, but also induces an increased expression of surface molecules on tumour cells. At 39 C, heat increases the MHC class I polypeptide-related sequence A (MICA), a molecule which increases cell sensitivity to natural killer cells [69,77]. At a temperature of 43 C, heat will increase the level of MHC class I molecules, which attract cytotoxic T-cells [69,78].…”