Indications of the Protective Role of Natural Killer Cells in Human Cutaneous Leishmaniasis in an Area of Endemicity

Abstract

The role of natural versus acquired immunity to Leishmania aethiopica infection in humans is the focus of our studies. We found in previous studies that mononuclear cells from nonexposed healthy Swedish donors responded to Leishmania antigen stimulation by proliferation and gamma interferon production. The main cell type responding was CD3− CD16/56+ natural killer (NK) cells. These findings led us to suggest that the potential to produce a rapid, nonacquired NK cell response may be a protective phenotype. In order to test this hypothesis, an area in Ethiopia whereLeishmania is endemic was selected, and peripheral blood mononuclear cells were obtained from individuals who had lived in the area most of their lives but had no evidence of past or present leishmaniasis. Their responses were compared with those of confirmed leishmaniasis patients from the same region with active lesions or cured leishmaniasis lesions. Cells from these donors were stimulated in vitro with L. aethiopica antigen. Responses were measured by proliferation, cytokine production, and phenotype analysis by fluorescence-activated cell sorting. The association ofNRAMP1 alleles with the studied phenotype and susceptibility to L. aethiopica-induced leishmaniasis was also evaluated. The results show that Leishmania antigens can induce NK cell and CD8+-T-cell responses in vitro. This is clearly seen in proliferating cells from the cured (immune) individuals and the apparently protected controls from the area of endemicity. It contrasted with the reactivity of the patients, where some NK proliferation was coupled with enhanced CD4+-T-cell proliferation. We conclude from these observations that NK cells and CD8+ cells proliferating in response toLeishmania stimulation are involved in protection from and healing of (Ethiopian) cutaneous leishmaniasis; however, such mechanisms appear to be unrelated to the NRAMP1 host resistance gene.

Natural killer cells in cross-regulation of IL-12 by IL-10 inLeishmaniaantigen-stimulated blood donor cells

“…This response has previously been shown to include NK cell activation and features of innate immune responses [18,26], although some T-cell responses were also noted in these responses. The importance of NK cells in this infection has recently been illustrated in an endemic situation 532 H. Akuffo et al where a potential role of NK cells in protection against human L. aethiopica induced disease was demonstrated [27]. We con®rm these ®ndings and show that strong in vitro responses to leishmanial antigens are reduced when NK cells are depleted from PBMC of unexposed donors.…”

Leishmania surface protein gp63 binds directly to human natural killer cells and inhibits proliferation

“…The variation in responses between individuals was extremely large; thus, to achieve significant differences between groups the sample sizes also need to be extremely large, with previous reports supporting the results reported here implicating an inhibition of NK cells during CL [21]. We followed-up this trend and tested if the L. major parasite may have an inhibitory effect on NK cells and mechanisms that may lie behind inhibition.…”

“…However, the role of NK cells in human infection is yet to be elucidated, but there are signs of suppression of NK cells and their release of cytokines such as IFN-g in patients infected with L. aethiopica, causing CL [21] and L. major. The decrease in numbers of NK cells in the blood of patients with active disease reported by Maasho et al [21] may be explained in several ways, including: (i) NK cells die to a higher extent or (ii) the receptors characteristic for NK cells are down-regulated, thus they cannot be identified during active infection. The in vitro results following exposure of L. major promastigotes to NK cells, which showed significantly lower expression levels of certain receptors, is consistent with the second possibility.…”

Compartmentalized cytotoxic immune response leads to distinct pathogenic roles of natural killer and senescent CD8+ T cells in human cutaneous leishmaniasis

“…The protective role of NK cells during CL is demonstrated by the increased proliferative activity in cured individuals compared with patients with active lesions. 9 Furthermore, higher numbers of CD56 + cells are found in the peripheral blood of patients with CL before and after treatment, 10 as well as in lesions of patients with diffuse CL who have a positive response to immunotherapy. 11 Conversely, increased NK cell activity is linked to susceptibility and severity of human visceral leishmaniasis, 12 CL 13,14 and mucocutaneous leishmaniasis.…”