IL-4R signaling is required to induce IL-10 for the establishment of T(h)2 dominance.
The requirement for IL-4 to promote differentiation of naive CD4(+) T cells into T(h)2 effector cell populations was established by classical in vitro studies. More recent in vivo data, however, indicate that signaling through the IL-4R is not essential for acquisition of the T(h)2 phenotype. In order to reconcile these seemingly contradictory conclusions, we have taken advantage of the ability of the excretory/secretory antigens of the gastrointestinal nematode Nippostrongylus brasiliensis to down-regulate T(h)1 cell development and drive T(h)2 cell expansion. We show that the initial development of IL-4-producing T cells is independent of IL-4R signaling but that the subsequent expansion of IL-4-producing CD4(+) T cells in a competitive environment that also contains T(h)1 potential is positively influenced by IL-4R signaling. We find that the production of IL-10 is the key IL-4R-dependent factor required to maintain T(h)2 dominance and that in the absence of IL-4R signaling, T(h)2 expansion can only be achieved by neutralization of T(h)1 cytokines. Moreover, in the absence of IL-4R signaling, reduced IL-10 production is due to the lack in expansion of an IL-10(+) T(h)2 population, rather than a global defect in the production of IL-10 by CD4(+) T cells. Thus, the evolution of T(h)2 dominance is achieved at the expense of T(h)1 cell development, normally restrained by IL-10 in an IL-4R-dependent manner. We conclude that T(h)2 cell development in response to N. brasiliensis antigen requires both IL-4 and IL-10 to act in concert on incipient populations of both T(h)1 and T(h)2 types.
Balic
Adam
A
Institute of Immunology and Infection Research, Ashworth Laboratories, West Mains Road, University of Edinburgh, EH9 3JT, UK.
Harcus
Yvonne M
YM
Taylor
Matthew D
MD
Brombacher
Frank
F
Maizels
Rick M
RM
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D005260:Female; D016753:Interleukin-10 / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009559:Nippostrongylus / Q000276:immunology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D017206:Strongylida Infections / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000382:microbiology*; D053662:Interleukin-4 Receptor alpha Subunit
D016753:Interleukin-10; D015847:Interleukin-4; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit