CD56^brightCD16^– NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation

Abstract

Psoriasis is an immune-mediated skin disease characterized by lymphocytic infiltration and altered keratinocyte differentiation. Using immunohistochemical techniques we found that the cellular infiltrate in acute psoriatic plaques includes 5-8% CD3 -CD56 + natural killer (NK) cells, mostly localized in the mid and papillary dermis. NK lymphocytes isolated from punch biopsy specimens of psoriatic plaques showed a CD56 bright CD16 -CD158b -phenotype, failed to express the skin homing cutaneous lymphocyte-associated antigen and released abundant IFN-c upon stimulation. Supernatants from psoriatic NK cells induced MHC class II and ICAM-1 expression and release of CXCL10 and CCL5 by cultured psoriatic keratinocytes. Skin NK cells expressed high levels of the chemokines receptors CXCR3 and CCR5, intermediate amounts of CXCR1, CCR6 and CCR8, and low levels of CCR1, CCR2, CCR4, CCR7 and CX3CR1. In addition, they promptly migrated in vitro toward CXCL10, CCL5, supernatants of IFN-c-activated psoriatic keratinocytes and, to a lower extent, CCL20 and CCL4. In contrast, they failed to migrate toward CXCL8, CCL1, CCL2, CCL3, CCL17, CCL19 and CX3CL1. Taken together, our results implicate NK lymphocytes as newly identified protagonists in the pathogenesis of psoriasis. Their distinctive homing properties should be taken into account in the design of specific therapy aimed at blocking pathogenic cell accumulation in the skin.

Klebsiella pneumoniae‐triggered DC recruit human NK cells in a CCR5‐dependent manner leading to increased CCL19‐responsiveness and activation of NK cells

“…DC maturation induced by IFN-g/FMKp led to an enhanced (41.5-fold increase in chemiluminescence) secretion of eleven chemokines as compared with TNF-a/PGE2-induced maturation. These chemokines included CCL5, CXCL10 and CCL19 to which NK cells can respond [23][24][25]. Quantification with ELISA confirmed that these chemokines were indeed produced by IFN-g/FMKp-matured DC and not by TNF-a/PGE2-matured DC (Fig.…”

“…However, during inflammation, it has been demonstrated that NK cells are able to migrate into inflamed tissue and draining lymph nodes [7,23]. Currently, it remains unclear what drives human NK-cell migration in vivo.…”

“…Blocking of CXCR3 did not affect NK-cell migration to IFN-g/FMKp-matured DC; therefore, our data suggest that CXCR3-and CCR5-dependent NK-cell recruitments are two different mechanisms by which NK cells can be attracted by DC. Both chemokine receptors CXCR3 and CCR5 are expressed by subpopulations of resting and activated NK cells and have been proven essential for NK-cell migration to various tissues in response to proinflammatory stimuli [23,26,32]. Which NK-cell-recruitment mechanism is utilized seems to depend on the agents used in DC maturation and lack of NKcell recruitment by TNF-a/PGE2-matured DC suggests that TLR ligands or other PRR-triggering agents are necessary triggers for DC to recruit NK cells.…”

CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

“…The bulk of CD56 bright are probably end-stage effector cells with an important role in restricting infections through monokine-induced cytokine production that guide the adaptive immune response [6]. Indeed, viral infections strongly impact the composition of the pool of CD56 bright [39][40][41] that can be found at inflammatory sites in contact with APC in a wide variety of inflammatory diseases [6,42,43].NK cells after HSCT express high levels of CD56 [27-30, 32, 33]. This has often been used as an argument that ptCD56 bright are immature [29,31,32,34].…”

Early viral replication in lymph nodes provides HIV with a means by which to escape NK‐cell‐mediated control

“…In mice, recruitment of NK cells to LNs depends on CD62L and CXCR3 [32]. Furthermore, CCR1 [33], CCR5 [34,35], CCR7 [36], CXCR1 [37], CX 3 CR1 [38], LPAM-1 (a4b7 integrin) [39], and CD103 (aEb7 integrin) [40] have also been implicated in recruitment of NK cells to sites of inflammation. Surprisingly, NK cells in HIV 1 individuals exhibited reduced CX 3 CR1 (po0.01) and CXCR1 (po0.01) expression compared with uninfected controls, suggesting that despite HIV-associated inflammation, NK cells may have a reduced capacity to migrate to the LN due to reduced expression of chemokine receptors that are critical for homing to lymphoid tissues and sites of inflammation (Fig.…”