J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/02/439/14 $2.00
Volume 185 February 1997 439-452

Novel Genetic Regulation of  T Helper 1 (Th1)/Th2 Cytokine Production and Encephalitogenicity in Inbred Mouse Strains

By Irina M. Conboy,^* Rosemarie H. DeKruyff, Keri M. Tate,^* Zhu A. Cao,^* Tom A. Moore,^§ Dale T. Umetsu, and Patricia P. Jones^*

From the ^* Department of Biological Sciences, Stanford University, Stanford, California 94305-5020;  Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305-5119; and ^§ DNAX Research Institute, Palo Alto, California 94304

Development of T helper cell (Th)1 or Th2 cytokine responses is essential for effector and regulatory functions of T helper cells. We have compared cytokine profiles of myelin basic protein (MBP) Ac1-16 peptide-specific T helper cells from inbred mouse strains expressing identical k haplotype-derived MHC class II molecules B10.A and B10.BR. B10.BR T cell lines (TCL) produced Th1 cytokines (including high levels of TNF-) and induced experimental autoimmune encephalomyelitis after adoptive transfer. In contrast, B10.A TCL produced Th2 cytokines (including low levels of TNF-) and were poorly encephalitogenic. The contributions of the genetic origin of the T cells and the APC were explored. Serial restimulations of the B10.BR TCL with B10.A or (B10.A × B10.BR) F1 splenic antigen presenting cells (APC) during the establishment of TCL markedly reduced both Th1 cytokine production and encephalitogenicity. In addition, a single restimulation with B10.A splenic APC reduced IFN- and TNF- production by established Th1 MBP-specific A^k-restricted B10.BR TCL and by a Th1 KLH-specific, E^k-restricted B10.BR T cell clone. These studies suggest that B10.A and B10.BR APC differ in their ability to stimulate IFN- and TNF- production by mature Th1 cells and also influence their Th1/Th2 commitment in vivo. The nature of the downregulatory activity of B10.A APC on IFN- and TNF- production was explored. 2-hour supernatants from antigen-activated B10.A APC/TCL cultures or from B10.A APC activated by LPS had the same inhibitory effects on IFN- and TNF- production by B10.BR TCL. The downregulatory effects of B10.A APC are independent of TNF-, IL-4, IL-10, IL-12p40, IFN-, IL-13, TGF-, and PGE2. Thus, genetic difference(s) between B10.A and B10.BR APC appear(s) to control the production or activity of a novel soluble cytokine regulatory factor that influences Th1/Th2 commitment and controls production of IFN- and TNF- by mature Th1 cells.

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