Helminth products bypass the need for TSLP in Th2 immune responses by directly modulating dendritic cell function.
Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine, mainly expressed by epithelial cells, and key to the development of allergic responses. The well-documented involvement of TSLP in allergy has led to the conviction that TSLP promotes the development of inflammatory Th2 cell responses. However, we now report that the interaction of TSLP with its receptor (TSLPR) has no functional impact on the development of protective Th2 immune responses after infection with 2 helminth pathogens, Heligmosomoides polygyrus and Nippostrongylus brasiliensis. Mice deficient in the TSLP binding chain of the TSLPR (TSLPR(-/-)) exhibited normal Th2 cell differentiation, protective immunity and memory responses against these two distinct rodent helminths. In contrast TSLP was found to be necessary for the development of protective Th2 responses upon infection with the helminth Trichuris muris (T. muris). TSLP inhibited IL-12p40 production in response to T. muris infection, and treatment of TSLPR(-/-) animals with neutralizing anti-IL-12p40 monoclonal antibody (mAb) was able to reverse susceptibility and attenuate IFN-gamma production. We additionally demonstrated that excretory-secretory (ES) products from H. polygyrus and N. brasiliensis, but not T. muris, were capable of directly suppressing dendritic cell (DC) production of IL-12p40, thus bypassing the need for TSLP. Taken together, our data show that the primary function of TSLP is to directly suppress IL-12 secretion, thus supporting Th2 immune responses.
Massacand
Joanna C
JC
Environmental Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology of Zurich, Wagistrasse 25, 8952 Schlieren, Switzerland.
Stettler
Rebecca C
RC
Meier
Reto
R
Humphreys
Neil E
NE
Grencis
Richard K
RK
Marsland
Benjamin J
BJ
Harris
Nicola L
NL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism* / Q000502:physiology*; D003713:Dendritic Cells / Q000166:cytology* / Q000469:parasitology*; D007107:Immune System; D007371:Interferon-gamma / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009559:Nippostrongylus; D017206:Strongylida Infections / Q000097:blood*; D018418:Th2 Cells / Q000378:metabolism* / Q000469:parasitology*; D014257:Trichuriasis / Q000097:blood*; D014258:Trichuris; D000094632:Thymic Stromal Lymphopoietin
D000911:Antibodies, Monoclonal; D016207:Cytokines; D053762:Interleukin-12 Subunit p40; D007371:Interferon-gamma; D000094632:Thymic Stromal Lymphopoietin