Leishmania major‐specific CD8⁺ T cells are inducers and targets of nitric oxide produced by parasitized macrophages

Abstract

Lines of Leishmania major-specific CD8+ T cells were derived from the lymph nodes and spleens of CBA mice, immune following resolution of a primary infection, 7 days after secondary challenge with viable L. major. Specific stimulation of these CD8+ T cells by bone marrow-derived macrophages infected with L. major led to the release of interferon-gamma by CD8+ T cells and nitric oxide by macrophages. Interestingly, the nitric oxide released by bone marrow-derived macrophages down-regulated the production of interferon-gamma by specifically activated CD8+ T cells. The proliferation and long-term maintenance of these parasite-specific CD8+ T cells was impaired by the nitric oxide produced by stimulating infected macrophages as a result of cytokines released by activated stimulating infected macrophages as a result of cytokines released by activated CD8+ T cells. Taken together, the results indicate that L. major-specific CD8+ T cells are sensitive to the toxic effect of the nitric oxide that they induce.

Antigen Requirements for Efficient Priming of CD8+T Cells byLeishmania major-Infected Dendritic Cells

“…This observation is in agreement with the specialized capacity of DC to present exogenous antigens to CD8 ϩ T cells (13,34). Prior studies using infected macrophages to activate CD8 ϩ T cells in each case used primed CD8 ϩ T cells (7,20,40), suggesting that whereas DC may be necessary to prime naïve CD8 ϩ T cells, infected macrophages can present MHC class I-restricted epitopes to trigger cytokine release from CD8 ϩ effector T cells and thus be activated for killing. We confirmed these observations by showing that at a high MOI, infected Mø can present NT-OVA to primed OT-I T cells, though 20-fold-less efficiently than DC.…”

“…In each case, however, the concentration of NT-OVA available for processing following uptake of heat-killed parasites or parasites expressing nonsecreted NT-OVA will be low compared to NT-OVA actively secreted by live parasites that can accumulate within the vacuole and enter the phagosome-associated MHC class I-restricted presentation pathway (1,18,19). Previous work using poorly defined antigens (e.g., live parasites or whole cellular extracts) suggested that secreted and cell surface-associated Leishmania antigen, but not nonsecreted antigens, were presented by APC to CD8 ϩ T cells (7,16,20,23,40) and CD4…”

Ubiquitin Conjugation of Open Reading Frame F DNA Vaccine Leads to Enhanced Cell-Mediated Immune Response and Induces Protection against Both Antimony-Susceptible and -Resistant Strains ofLeishmania donovani

“…Resistance to leishmaniasis has been associated with a predominant IL-12 and IFN-␥ production from the Ag-specific CD4 ϩ Th lymphocyte population termed as Th1 immune response (61,62). These cells along with CD8 ϩ T cytotoxic lymphocytes are then effective in promoting macrophage activation, and the intracellular Leishmania are killed in a NO-dependent manner (63)(64)(65).…”

Differences in Gamma Interferon Production In Vitro Predict the Pace of the In Vivo Response toLeishmania amazonensisin Healthy Volunteers

“…Natural killer cells may be a very important source of IFN-␥ in this situation. While previous reports have shown that CD8 ϩ T cells may not be essential for primary immunity (17), there have been several studies which have shown that CD8 ϩ T cells do have a role in secondary responses (24,25,34). LACK DNA induces antigen-specific CD8…”