Th1 cell anergy and blockade in G1a phase of the cell cycle.

Human gamma-globulin (HGG)-specific Th1 cells exposed to HGG presented by chemically fixed spleen cells are blocked in G1a phase when challenged subsequently with HGG. The present study made use of the G1a blocker n-butyrate to further examine the relationship between tolerance induction and cell cycle progression. Th1 cells from primary cultures containing n-butyrate together with HGG and immunogenic, nonfixed APC lost their ability to proliferate or secrete IL-2 in HGG-stimulated secondary cultures. In contrast to their lack of responsiveness to secondary Ag challenge, Th1 cells exposed to n-butyrate and HGG proliferated normally in secondary cultures stimulated with IL-2. The suppressive effects of n-butyrate appear to require TCR occupation; Th1 cells exposed to n-butyrate in the absence of HGG did not lose their ability to proliferate in Ag-stimulated secondary cultures. In addition, although both HGG-presenting APC and IL-2 stimulate Th1 cell cycle progression into G1a, only HGG-presenting APC induced Th1 cell anergy in conjunction with n-butyrate. Unlike n-butyrate, drugs that blocked Th1 cell cycle progression in G0, G1b, or S/G2 phases did not inhibit subsequent Ag-specific proliferation by Th1 cells. Thus it appears that n-butyrate-induced G1a sequestration, in association with TCR occupancy, induces Th1 cell anergy.