Abstract
Disease progression in response to infection can be strongly influenced by both pathogen burden and infection-induced immunopathology. While current therapeutics focus on augmenting protective immune responses, identifying therapeutics that reduce infection-induced immunopathology are clearly warranted. Despite the apparent protective role for murine CD8+ T cells following infection with the intracellular parasite Leishmania, CD8+ T cells have been paradoxically linked to immunopathological responses in human cutaneous leishmaniasis. Transcriptome analysis of lesions from Leishmania braziliensis patients revealed that genes associated with the cytolytic pathway are highly expressed and CD8+ T cells from lesions exhibited a cytolytic phenotype. To determine if CD8+ T cells play a causal role in disease, we turned to a murine model. These studies revealed that disease progression and metastasis in L. braziliensis infected mice was independent of parasite burden and was instead directly associated with the presence of CD8+ T cells. In mice with severe pathology, we visualized CD8+ T cell degranulation and lysis of L. braziliensis infected cells. Finally, in contrast to wild-type CD8+ T cells, perforin-deficient cells failed to induce disease. Thus, we show for the first time that cytolytic CD8+ T cells mediate immunopathology and drive the development of metastatic lesions in cutaneous leishmaniasis.
Highlights
CD8+ T cells contribute to the control of pathogens by cytokine production, cytolytic activity or both
To better understand the local immune environment during human leishmaniasis and the extent to which a cytolytic program is associated with the infection, we carried out whole genome expression profiling of lesions from patients infected with L. braziliensis
We found a significant increase in CD8+ T cells expressing surface CD107a from lesions, while CD8+ T cells from the blood failed to express CD107a (Fig. 1E). These results confirm previous studies showing that CD8+ T cells express granzyme in leishmaniasis [15], and extend these findings to show that the CD8+ T cells are cytolytically active within human leishmanial lesions
Summary
CD8+ T cells contribute to the control of pathogens by cytokine production, cytolytic activity or both. In the case of intracellular parasites, the production of IFN-c by CD8+ T cells is protective, while in viral infections CD8+ T cells provide protection by inducing cytokine production and killing virally infected cells [1] These same CD8+ T cell effector functions can promote increased pathology, and the presence of CD8+ T cells has been associated with increased pathology in several infectious and autoimmune diseases [2,3,4,5,6,7,8]. A great deal is known about how leishmania parasites are eliminated Control of these intracellular parasites requires a CD4+ Th1 cell response, which leads to IFN-c production that enhances the killing capacity of infected macrophages and dendritic cells [9,10]. Correlations with enhanced immunopathology and lower levels of IL-10 or IL-10 receptor expression have been observed in patients, but the unregulated responses that promote pathology are not defined [13,14]
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