The capacity to produce IFN-gamma rather than the presence of interleukin-4 determines the resistance and the degree of susceptibility to Leishmania donovani infection in mice.
The immune response against Leishmania donovani infection has been investigated in one resistant mouse strain (C3H/HeJ) and three susceptible mouse strains (C57BL/6, BALB/c, and B10D2/n). In order to correlate the strain-specific course of infection with the individual T cell response phenotype, the ex vivo cytokine secretion patterns of splenic lymphocytes were assessed by ELISA (interferon-y [IFN-gamma], interleukin-4 [IL-4], IL-10) or by bioassay (IL-2). The strain-dependent differences in the course of infection correlated closely with the potency of T cells to produce IFN-gamma. C3H/HeJ mice produced high amounts of IFN-gamma before and during infection, whereas susceptible mice produced low amounts of IFN-gamma early during L. donovani infection. However, C57BL/6 mice, which recovered from the infection rapidly after the acute stage, developed marked IFN-gamma response within the first 30 days of infection. In contrast, in BALB/c and B10D2/n mice, the IFN-gamma production diminished during the acute stage, and this was associated with a delay in recovery and with subsequent switching into the chronic stage. Interestingly, CD8+ T cells contributed significantly to IFN-gamma production during this phase. In contrast to IFN-y, the levels of IL-4 in response to antigen or mitogen ex vivo were always very low. Moreover, neutralization of endogenous IL-4 in vivo by treatment with soluble murine IL-4 receptor did not result in significant decreases in the parasite burdens in spleen and liver but did cause a decrease in the serum IgE level of L. donovani-infected BALB/c mice. These results confirm that in visceral leishmaniasis a Thl-dominated immune response is protective against the L. donovani parasites and, furthermore, that the capacity to produce IFN-gamma rather than the presence of IL-4 determines the efficacy of the immune response in susceptible mice. The data show that CD8+ T cells represent an important source of IFN-gamma during L. donovani infection in susceptible mice, implying a role for this cell type in healing and development of protective immunity.
Lehmann
J
J
Fraunhofer Institute for Toxicology and Aerosolresearch Hannover, Department of Immunobiology, Germany. Lehj@medizin.uni-leipzig.de
Enssle
K H
KH
Lehmann
I
I
Emmendörfer
A
A
Lohmann-Matthes
M L
ML
D000208:Acute Disease; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003289:Convalescence; D005260:Female; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology*; D007893:Leishmania donovani / Q000276:immunology / Q000472:pathogenicity*; D007898:Leishmaniasis, Visceral / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D019948:Receptors, Interleukin-4 / Q000008:administration & dosage / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014774:Virulence
D000913:Antibodies, Protozoan; D007074:Immunoglobulin G; D007376:Interleukin-2; D019948:Receptors, Interleukin-4; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma