Costimulation via TCR and IL-1 receptor reveals a novel IL-1alpha-mediated autocrine pathway of Th2 cell proliferation.
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-1alpha, as detected at the level of function, protein, and mRNA expression. In the presence of the TCR signal, autocrine IL-1alpha 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.
Huber
M
M
Institut für Klinische Mikrobiologie und Immunologie, Friedrich Alexander Universität Erlangen, Germany.
Beuscher
H U
HU
Rohwer
P
P
Kurrle
R
R
Röllinghoff
M
M
Lohoff
M
M
D000818:Animals; D019898:Autocrine Communication / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002999:Clone Cells; D007375:Interleukin-1 / Q000276:immunology / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000502:physiology*
D007375:Interleukin-1; D011948:Receptors, Antigen, T-Cell; D017472:Receptors, Interleukin-1