NOVEL GENETIC-REGULATION OF T-HELPER-1 (TH1) TH2 CYTOKINE PRODUCTION AND ENCEPHALITOGENICITY IN INBRED MOUSE STRAINS/

Development of T helper cell (Th)1 or Th2 cytokine responses is essent ial for effector and regulatory functions of T helper cells. We have c ompared cytokine profiles of myelin basic protein (MBP) Ac1-16 peptide -specific T helper cells from inbred mouse strains expressing identica l 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 TN F-alpha) and induced experimental autoimmune encephalomyelitis after a doptive transfer. In contrast, B10.A TCL produced Th2 cytokines (inclu ding low levels of TNF-alpha) and were poorly encephalitogenic. The co ntributions of the genetic origin of the T cells and the APC were expl ored. Serial restimulations of the B10.BR TCL with B10.A or (B10.A X B 10.BR) F1 splenic antigen presenting cells (APC) during the establishm ent of TCL markedly reduced both Th1 cytokine production and encephali togenicity. In addition, a single restimulation with B10.A splenic APC reduced IFN-gamma and TNF-alpha production by established Th1 MBP-spe cific A(k)-restricted B10.BR TCL and by a Th1 KLH-specific, E(k)-restr icted B10.BR T cell clone. These studies suggest that B10.A and B10.BR APC differ in their ability to stimulate IFN-gamma and TNF-alpha prod uction by mature Th1 cells and also influence their Th1/Th2 commitment in vivo. The nature of the downregulatory activity of B10.A APC on IF N-gamma and TNF-alpha production was explored. 2-hour supernatants fro m antigen-activated B10.A APC/TCL cultures or from B10.A APC activated by LPS had the same inhibitory effects on IFN-alpha and TNF-alpha pro duction by B10.BR TCL. The downregulatory effects of B10.A APC are ind ependent of TNF-alpha, IL-4, IL-10, IL-12p40, IFN-gamma, IL-13, TGF-be ta, 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 cy tokine regulatory factor that influences Th1/Th2 commitment and contro ls production of IFN-gamma and TNF-alpha by mature Th1 cells.