One of the hallmarks of adaptive immunity is the development of a long-term pathogen specific memory response. While persistent memory T cells certainly impact the immune response during a secondary challenge, their role in unrelated infections is less clear. To address this issue, we utilized lymphocytic choriomeningitis virus (LCMV) and Listeria monocytogenes immune mice to investigate whether bystander memory T cells influence Leishmania major infection. Despite similar parasite burdens, LCMV and Listeria immune mice exhibited a significant increase in leishmanial lesion size compared to mice infected with L. major alone. This increased lesion size was due to a severe inflammatory response, consisting not only of monocytes and neutrophils, but also significantly more CD8 T cells. Many of the CD8 T cells were LCMV specific and expressed gzmB and NKG2D, but unexpectedly expressed very little IFN-γ. Moreover, if CD8 T cells were depleted in LCMV immune mice prior to challenge with L. major, the increase in lesion size was lost. Strikingly, treating with NKG2D blocking antibodies abrogated the increased immunopathology observed in LCMV immune mice, showing that NKG2D engagement on LCMV specific memory CD8 T cells was required for the observed phenotype. These results indicate that bystander memory CD8 T cells can participate in an unrelated immune response and induce immunopathology through an NKG2D dependent mechanism without providing increased protection.
Cutaneous leishmaniasis has a wide spectrum of clinical presentations, from mild self-healing lesions to severe chronic infections. Differences in each individual's response are related to pathogen dose and the genetic and physiological status of the host, but exactly what causes the broad spectrum of disease is not well understood. Here we show that previous infection with a viral or bacterial pathogen led to increased immunopathology associated with L. major infection. This increase in immunopathology was not associated with any changes in parasite control and was characterized by an exaggerated inflammatory infiltrate into the site of infection. Ultimately, this increase in immunopathology was dependent on the presence of memory CD8 T cells from the previous infection and their expression of the NK cell receptor NKG2D, as depletion of these cells prior to infection with L. major or blockade of this receptor during infection ameliorated the disease. Our work suggests that the immunological history of a patient may be playing an underlying role in the pathology associated with leishmania infection and could be an important consideration for the understanding and treatment of this and other human diseases. This work also identifies the NKG2D pathway as a potential new target for therapeutic intervention.