Control of parasitemia and survival during Trypanosoma brucei brucei infection is related to strain-dependent ability to produce IL-4.
We studied non-MHC gene-dependent expression of a number of cytokines in relation to host defense and survival during Trypanosoma brucei brucei (Tbb) infection in mice. In particular, the role of IL-4 was explored with use of genomically IL-4-disrupted mice and in vivo Ab blocking. Splenocytes from MHC-identical B10.Q (relatively resistant) mice showed day 5 postinfection higher numbers of IL-4 mRNA expressing cells than C3H.Q (highly susceptible). A trypanosome-derived lymphocyte triggering factor, which is released by Tbb to polyclonally activate CD8+ T cells, stimulated naive splenocytes in vitro to a higher IL-4 response in B10.Q than in C3H.Q mice. The C3H.Q mice developed an extremely high parasitemia, showed a low Ab response against the variant surface glycoprotein (VSG), and had a mean survival time of 42 days. Conversely, B10.Q mice had lower parasitemia, mounted higher anti-VSG response, and had a mean survival time of 56 days. Deletion of the IL-4 gene had no influence on the infection in C3H.Q mice, while in B10.Q mice the deletion was associated with lower anti-VSG Ab levels and higher parasitemia. Paradoxically, B10.Q mice with disrupted IL-4 gene survived longer than the wild type. Anti-IL-4 Ab-blocking experiments in vivo displayed an enhanced parasitemia and prolonged survival in infected B10.Q mice. We conclude that 1) a non-MHC gene-related and CD8+-dependent ability to produce IL-4 partly determines the susceptibility to Tbb infection; and 2) IL-4, although involved in controlling the levels of parasitemia by its effects on immunoglobulin synthesis, also can have toxic effects on the animals.
Bakhiet
M
M
Molecular Medicine Unit, Department of Medicine, Karolinska Hospital, Stockholm, Sweden. Moiz.Bakhiet@cnsf.ki.se
Jansson
L
L
Büscher
P
P
Holmdahl
R
R
Kristensson
K
K
Olsson
T
T
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000913:Antibodies, Protozoan / Q000096:biosynthesis; D016207:Cytokines / Q000235:genetics; D005260:Female; D017403:In Situ Hybridization; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018512:Parasitemia / Q000276:immunology* / Q000469:parasitology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D014346:Trypanosoma brucei brucei; D014353:Trypanosomiasis, African / Q000276:immunology* / Q000469:parasitology; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000276:immunology
D019138:Antibodies, Blocking; D000913:Antibodies, Protozoan; D016207:Cytokines; D012333:RNA, Messenger; D014643:Variant Surface Glycoproteins, Trypanosoma; D015847:Interleukin-4