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.