Tick saliva inhibits differentiation, maturation and function of murine bone‐marrow‐derived dendritic cells

Abstract

SummaryHaematophagous arthropod vectors such as mosquitoes, tsetse flies, sandflies and ticks have evolved salivary immunomodulatory factors that prevent the vertebrate host from rejecting them meanwhile enhancing pathogen transmission. As dendritic cells (DC) play a major role in host immune responses, we studied the effects of Rhipicephalus sanguineus tick saliva on DC differentiation and maturation. Flow cytometry analysis revealed that the addition of saliva to bone marrow cells inhibits the differentiation of DC and decreased the population of differentiated immature DC, increasing the levels of major histocompatibility complex (MHC) class II while not altering the expression of costimulatory (CD40, CD80 and CD86) and adhesion (CD54) molecules. Furthermore, maturation of DC stimulated by lipopolysaccharide (LPS) in the presence of saliva resulted in a lower expression of costimulatory molecules, but did not alter the up-regulation of MHC class II and CD54. The lipopolysaccharide (LPS)-matured DC cultured with saliva also presented reduced production of interleukin-12, whereas interleukin-10 production was unaltered. Assessment of the function of DC cultured with tick saliva revealed them to be poor stimulators of cytokine production by antigen-specific T cells. Our data indicate a novel modulatory role for the saliva of arthropod vectors at an initial step of the immune response through the inhibition of differentiation and maturation of DC into functional antigen-presenting cells. Keywordsbeen shown that tick-infested mice do not develop resistance to further infestations with R. sanguineus, and that the immune response in infested mice is of a T helper 2 (Th2) pattern. 21 However, knowledge of the effect of tick saliva on dendritic cells (DC), the most potent antigenpresenting cell (APC), and the initiators of the immune response, is lacking.In the last few years, a number of new procedures have been described in order to obtain DC, starting from haemopoietic progenitor cells of peripheral blood or bone marrow (BM), 22 by culturing them with tumour necrosis factor-a (TNF-a) + granulocyte-macrophage colonystimulating factor (GM-CSF) or IL-4 + GM-CSF. [23][24][25] These cultured DC present functional and phenotypic features of an immature stage of differentiation (i.e. a high capacity of antigen uptake and processing, and a low capacity to stimulate T-cell proliferation) and can be further differentiated in vitro into mature DC if stimulated with TNF-a, lipopolysaccharide (LPS), IL-1 or CD40L. 23,26 During tick feeding, salivary antigens are introduced into the host skin and may be captured and processed by epidermal APC, such as DC (Langerhans' cells) and macrophages, which can subsequently migrate to the draining lymph nodes and present them to antigen-specific T lymphocytes. In effect, the skin and draining lymph nodes of tick-infested animals may contain cells that stain for tick salivary antigens. 27 Moreover, ultraviolet radiation prior to an initial tick infestation significantly reduces the acquisi...

Prostaglandin E2 Is a Major Inhibitor of Dendritic Cell Maturation and Function in Ixodes scapularis Saliva

“…Tick saliva also modulates cytokine production by epidermal cells (35) and alters expression of adhesion molecules by skin-derived endothelial cells (36). More recently, a study demonstrated that saliva from R. sanguineus inhibits differentiation, maturation, and cytokine synthesis of bone marrow-derived DCs (20). Despite the critical role of immunomodulators in tick-host interaction, the molecular cloning and identification of most of these molecules have not been reported.…”

“…In addition, splenocytes from C3H/ HeJ mice infested with I. scapularis nymphs presented decreased production of IL-2 and IFN-␥ and increased production of IL-4 and IL-10 when stimulated with Con A (17,18). Also, saliva of Rhipicephalus sanguineus inhibited Con A-induced IL-2 production by splenocytes (19) and IL-12 production by LPS-stimulated bone marrow-derived DCs (20). Despite the potentially critical role of these molecules in the biology of tick feeding and host-vector interaction, their molecular identification has remained elusive to date.…”

Tick Saliva Inhibits Dendritic Cell Migration, Maturation, and Function while Promoting Development of Th2 Responses

“…The tick saliva has been reported to inhibit differentiation and LPS induced-maturation of bone marrow-derived DCs (BMDCs) in vitro (15). More recently, prostaglandin E 2 contained in the tick saliva has been found to impair cytokine production by BMDCs as well as their capacity to induce T cell proliferation (16).…”

“…Cavassani et al (15) described an inhibitory effect on DC differentiation and LPS induced maturation. More recently, it has been shown that prostaglandin E 2 present in tick saliva inhibits IL-12 and TNF-␣ production by DCs (16).…”

The Tick Salivary Protein Salp15 Inhibits the Killing of Serum-Sensitive Borrelia burgdorferi Sensu Lato Isolates

“…It has already been shown that they use Salp15 to inhibit the activation and proliferation of CD4 ϩ T cells by binding to its CD4 receptor (1,6,13). In addition, tick salivary proteins have been found to inhibit B cells (8), dendritic cells (4,11), NK cells (17), neutrophils (20), and macrophages (7). Isac (5,27) and Salp20 (26) are two salivary proteins that were shown to inhibit the alternative pathway of the complement system.…”