T cell-derived IL-3 induces the production of IL-4 by non-B, non-T cells to amplify the Th2-cytokine response to a non-parasite antigen in Schistosoma mansoni-infected mice.
We describe a novel amplification mechanism underlying the increased early IL-4 production observed in Schistosoma mansoni-infected mice in response to a non-parasite Ag, sperm whale myoglobin (SwMb). Earlier studies have shown that splenic Fc epsilon R+ non-B, non-T (NBNT) cells from schistosome-infected mice secrete IL-4 after stimulation with parasite Ag. We now demonstrate that purified NBNT cells from SwMb-immunized S. mansoni-infected mice do not respond directly to SwMb, but produce IL-4 in response to IL-3. Accordingly, we show that the early SwMb-specific IL-4 response of spleen cells (SC) from immunized infected mice is dependent on IL-3 and on CD4+ T cells. Thus, most of the early SwMb-induced IL-4 from SC of infected mice appears to be produced by NBNT cells triggered by IL-3 synthesized by SwMb-specific CD4+ T cells. IL-3-induced IL-4 production was also observed in purified NBNT cells from immunized uninfected mice, but the frequency and/or IL-4-producing capacity of splenic IL-3-responsive cells was found to be 8 to 16 times higher in immunized infected animals. IL-4 production by purified CD4+ cells from immunized infected mice was also seen after SwMb stimulation, but this response showed slower kinetics than those of total SC, was IL-3-independent, and on average threefold greater than that by CD4+ cells from immunized uninfected controls. Thus, increased SwMb-induced IL-4 production in immunized S. mansoni-infected mice results from direct synthesis by CD4+ T cells, as well as their stimulation via IL-3 of an expanded population of NBNT cells. The latter pathway may serve as an amplification loop for Th2-cytokine responses.
Kullberg
M C
MC
Immunobiology Section, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD 20892, USA.
Berzofsky
J A
JA
Jankovic
D L
DL
Barbieri
S
S
Williams
M E
ME
Perlmann
P
P
Sher
A
A
Troye-Blomberg
M
M
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D007377:Interleukin-3 / Q000502:physiology*; D015847:Interleukin-4 / Q000096:biosynthesis*; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009211:Myoglobin / Q000276:immunology; D017452:Receptors, IgG / Q000502:physiology; D012550:Schistosoma mansoni; D012555:Schistosomiasis mansoni / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D018418:Th2 Cells / Q000276:immunology*
D007377:Interleukin-3; D009211:Myoglobin; D017452:Receptors, IgG; D015847:Interleukin-4