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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 x 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-β, 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.

This work was supported by Multiple Sclerosis Society grant PP0454 to P.P. Jones and National Institutes of Health grants AI19512 to P.P. Jones, AI24571 to R.H. DeKruyff, and AI26322 to D.T. Umetsu. I. Conboy was supported by NIH training grants GM07276 and HD07249.

¹Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; LA^k, L cell fibroblast expressing A^k class II proteins; MBP, myelin basic protein; mMBP, mouse MBP; TCL, T cell line.

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