Monocyte Surface-Bound IL-15 Can Function as an Activating Receptor and Participate in Reverse Signaling

Abstract

IL-15 is a short chain, four-α helix cytokine that shares some biological function with IL-2. One striking difference between IL-2 and IL-15 is the ability of monocytes to express IL-15 on their cell surface after activation. In the current study we have investigated the ability of human monocyte cell surface IL-15 to participate in reverse signaling. Cross-linking anti-IL-15 Abs were used as a surrogate ligand for surface IL-15 engagement. Ligation of cell surface-expressed IL-15 induced monocyte adhesion that required the activity of small m.w. GTPases. Reverse signals through surface IL-15 activated the Rho-GTPase Rac3. In addition, engagement of cell surface IL-15 was found to activate a number of signaling pathways, including both extracellular signal-regulated kinase 1/2 and p38, and resulted in the secretion of IL-8. IL-8 production required mitogen-activated protein kinase activity. Thus, the current study has established that cell surface IL-15 is more than just a ligand; it can function as a receptor and participate in reverse signaling that results in cellular adhesion and production of inflammatory cytokines.

Membrane-bound IL-15 stimulation on peripheral blood natural kiler progenitors leads to the generation of an adherent subset co-expressing dendritic cells and natural kiler functional markers

“…This indicates that this form of mbIL-15 is retained at the membrane through an IL-15R-independent mechanism theoretically able to deliver a bidirectional signal. 13,14 Analysis of Online Supplementary Figure S1B confirms our previous results 10 showing that PB-HP, expanded at high cell density (2¥10 5 cells/mL) in the presence of stem cell factor (SCF) and FL, progressively lose the expression of the early hematopoietic markers CD34 and CD38 through reciprocal mbIL-15 trans-presentation. 10 Moreover, this culture condition is necessary and sufficient to commit these cells into the NK differentiation pathway in the absence of exogenous lymphokines, as shown by the progressive acquisition of the different functional markers that define the mature NK cells.…”

“…13 Flow cytometry analysis ( Figure 1B left panel) of the above mentioned adherent subset shows that these cells express the NK cell-specific marker NKp46 15 and myeloid DC specific markers CD1a 16 and BDCA1. 17 In addition, these cells express several other NK markers (CD56, CD16, CD161, NKp44 and perforin) as well as markers of immune activation (CD11c, HLA-DR, CD80, CD86, CD25) common to both cell types.…”

IL‐15‐induced human DC efficiently prime melanoma‐specific naive CD8+ T cells to differentiate into CTL

“…Thus, IL-15 might induce a unique set of DC molecules that facilitate priming. In addition, IL-15 itself acts, in the membranebound form, as a costimulatory molecule [15][16][17]. Indeed, sonicated IL15-DC express IL-15, suggesting the presence of a membrane-bound form that might be biologically active and therefore contribute to enhanced CTL priming.…”

“…10) but not in the culture supernatants (not shown) suggests the presence of membrane-bound IL-15. This form of IL-15 could be biologically active, as described previously [15][16][17], and therefore contribute to enhanced CD8 + T cell priming and differentiation. …”

Functional and immunophenotypic characteristics of NK cells from regional lymph nodes of melanoma patients and their in vitro activation with IL-2 and IL-15

“…da aktivira procese u ćeliji koja ga ispoljava kao i da tom prilikom aktivira signalne putanje Rho familije (Rac) kinaza i MAPK signalnog puta, kao i da može da aktivira međućelijsku adheziju i sintezu interleukina IL-8 u monocitima (Neely et al,2004). Pored toga, pokazano je da trans prezentovan IL-15 može i da recipročnom signalnom putanjom dovede do diferencijacije hematopoetskih prekursora NK ćelija u necitotoksične zrele regulatorne NK ćelije (NKireg) koje ispoljavaju imunosupresivni molekul HLA-G. Pokazano je da se ova malobrojna subpopulacija NKp46 (Giuliani et al,2008).…”