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Costimulation via TCR and IL-1 Receptor Reveals a Novel IL-1-Mediated Autocrine Pathway of Th2 Cell Proliferation¹

Magdalena Huber^*, Horst U. Beuscher^*, Peter Rohwer, Roland Kurrle, Martin Röllinghoff^* and Michael Lohoff^2,*

^* Institut für Klinische Mikrobiologie und Immunologie, and Medizinische Klinik III, Friedrich Alexander Universität Erlangen, Erlangen, Germany; and Hoechst-Marion-Roussel Rheumatologie, Wiesbaden, Germany

Previous studies have shown that triggering of Th2 cells via the TCR is sufficient for production of IL-4 but not for proliferation of these cells. Proliferation of Th2 cells occurs only in the additional presence of a costimulatory signal delivered by IL-1. For the majority of Th2 cell clones, this type of proliferation was found to be independent of IL-4. Here, we further investigated the mechanism of IL-4-independent proliferation. We demonstrate that, after costimulation via TCR and IL-1R, but not via either receptor alone, Th2 cells are triggered to produce cell-associated IL-1, as detected at the level of function, protein, and mRNA expression. In the presence of the TCR signal, autocrine IL-1 is then able to costimulate IL-4-independent proliferation of Th2 cells and to further enhance its own production. Thus, our results point to a novel, IL-4-independent, self-amplifying autocrine pathway of Th2 cell proliferation that requires a signal via the TCR and a costimulatory signal via IL-1R. This pathway may explain frustrating results in experimental models that attempted to treat established Th2-mediated diseases in vivo with IL-4-neutralizing agents alone.

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