Development of T_h1 and not T_h2 immune responses in mice lacking IFN-regulatory factor-4

IFN-regulatory factor (IRF)-4 is a member of the IRF family of transcription factors expressed in lymphocytes and macrophages. The previous studies using mice deficient in the IRF-4 gene showed profound defects in function of both B and T cells. To further investigate the role of IRF-4 in CD4⁺ T cell function, IRF-4^-/- mice were challenged with the intracellular pathogen Leishmania major. The mice were protected against L. major during the early phase of the infection and CD4⁺ T cells of the infected mice produced IFN-γ in response to L. major antigen. However, during the late phase of infection, lymphocyte numbers were dramatically reduced in the draining lymph nodes, resulting in the deterioration of the lesion, indicating that IRF-4 was required for sustained immune responses against L. major infection. The function of CD4⁺ T cells was further investigated using TCR transgenic mice lacking the IRF-4 gene. CD4⁺ T cells from IRF-4^-/- mice produced IFN-γ and expressed T-bet after culture under T_h1-skewing conditions in vitro. However, T_h2 cell development was not observed after culture under T_h2-polarizing conditions. Proliferation of CD4⁺ T cells to IL-4 was reduced in IRF-4^-/- mice, suggesting the defects in the responsiveness to IL-4. Furthermore, stimulation of the IRF-4^-/- CD4⁺ T cells with IL-⁴-induced activation of signal transducer and activator of transcription 6, but not expression of growth factor independent-1. Thus, development of CD4⁺ T cell subsets differentially depends on IRF-4; induction of T_h1 response does not depend on IRF-4, while T_h2 response depends entirely on IRF-4.