Oscillation of antibody production and regulatory T cells in response to antigenic stimulation.

Priming with the T-dependent antigen trinitrophenylated horse red blood cells led to an oscillatory response of plaque-forming cells (PFC) with peaks of response after 4, 8, 12 and 16 days. Limiting dilution (LD) analysis of regulatory T cells indicated that the response is partly due to activation of helper T cells (Th), but mainly is the result of release from suppression by activation of a third regulatory T cell (T3) population (Zöller, H. and Andrighetto, G., Immunology 1985. 55: 703). Priming resulted in consecutive activation of suppressor T cells (Ts; day 1-3), a population regulating Ts (T3; day 2-4) and of Th (day 4). Furthermore, regulatory elements displayed a cyclical behavior like PFC. Th and T3 oscillated within a period of 4 days in phase with PFC, while Ts oscillated phase-shifted to PFC, Th and T3. Hence, oscillation of PFC after priming with a T-dependent antigen is the result of interactions among regulatory T cells. The data are interpreted as follows. Th are the primum movens of the oscillatory behavior of PFC response, since Th oscillate in phase with PFC and display the same pattern of decreasing amplitudes as PFC. However, the basic regulatory elements are Ts and T3 which are interlinked and oscillate phase shifted. As revealed by the time-course analysis of LD curves, T3 function as suppressor cells for Ts. Hence the status of mutual interactions of Ts and T3 determines suppression of Th or release from suppression, i.e. when T3 are found at high frequencies, Th are released from suppression, since T3 suppresses Ts. Instead, the increase in the frequency of Ts and their predation on Th determine the decrease of the frequency of Th. Thus, these data support the hypothesis of a circular network, the central regulatory core being composed of two elements, Ts and T3, with mutual suppressive activity.