Pinpointing IL‐4‐independent acquisition and IL‐4‐influenced maintenance of Th2 activity by CD4 T cells

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Abstract
Naive CD4 T cells develop Th2 activity early in primary responses to alum‐precipitated proteins by producing IL‐4 mRNA and inducing B cells to produce γ1 and ϵ switch transcripts. BothIL‐4‐dependent and IL‐4‐independent pathways for IL‐4 induction are recognized, but their relative contribution to the different phases of primary Th2 responses in vivo is uncertain. We show the primary induction of IL‐4 synthesis in lymph nodes responding to alum‐precipitated protein is overwhelmingly in antigen‐specific CD4 T cells and is unimpaired in IL‐4Rα–/– mice, which can produce but do not respond to IL‐4 and IL‐13. Ig class‐switching in extra‐follicular responses, reflecting Th2 activity, is also unimpaired in these mice. By contrast, 7 days after immunization — when T cells are selecting B cells in germinal centers and T cell priming has occurred — non‐responsiveness to IL‐4 is associated with smaller germinal centers, increased levels of T‐bet andγ2a switch transcripts and reduced γ1 and ϵ transcripts. These data indicate that Th2 characteristics acquired during T cell priming and the initial CD4 T cell interaction with B cells are largely IL‐4‐independent, whereas IL‐4 production induced during priming has a significant role in maintaining the Th2 phenotype as T cells select B cells in germinal centers.