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Primary Role for Gi Protein Signaling in the Regulation of Interleukin 12 Production and the Induction of T Helper Cell Type 1 Responses

Correspondence to: Brian L. Kelsall, Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Rm. 11N238, 10 Center Dr., Bethesda, MD 20892-1890. Tel:301-496-7473 Fax:301-402-2240 E-mail:kelsall{at}nih.gov.

We explored the role of Gi protein signaling in the regulation of interleukin (IL)-12 production and T helper cell type 1 (Th1) T cell differentiation. In initial studies, we showed that treatment of normal mice with pertussis toxin (PT), which inhibits Gi protein signaling, enhanced the capacity of splenocytes to produce IL-12 in response to both microbial and nonmicrobial stimuli. In addition, PT treatment increased the production of tumor necrosis factor (TNF)- and IL-10 by stimulated cells. These findings were corroborated by the fact that untreated Gi2^2/- mice exhibited enhanced production of IL-12 and TNF- by splenocytes, and of IL-12 p40 by purified spleen CD8⁺ lymphoid dendritic cells. Finally, we showed that while normal BALB/c mice infected with Leishmania major exhibited a nonhealing phenotype, those treated with PT when infection was initiated exhibited a healing phenotype along with an enhancement of leishmania-specific Th1 responses in draining lymph nodes. Further, healing was prevented by coadministration of anti–IL-12 and PT. These data demonstrate that endogenous Gi protein signaling has a primary role in the regulation of IL-12 production and the induction of Th1 responses in vivo.

Key Words: G protein, interleukin 12, T helper cell type 1, pertussis toxin, leishmaniasis

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