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mAbs directed against the L3T4 molecule administered in vivo caused a severe and long lasting helper cell depletion in mice. Regeneration of the L3T4+ subpopulation occurred gradually (2-3 mo) after a single antibody treatment. Experiments were designed to examine the humoral immunocompetence of such anti-L3T4-treated animals during and after regeneration of the L3T4+ T cell subset. The animals were injected with anti-L3T4, immunized with soluble antigen, and challenged with antigen every 2 wk. Antibody responses to two antigens, sperm whale myoglobin (SpWMb) and KLH, which differ with regard to their immunogenicity, were compared. The lack of humoral immune responsiveness to either of these two antigens shorty after anti-L3T4 treatment responsiveness to either of these two antigens shortly after anti-L3T4 treatment was probably due to clonal depletion. The anti-L3T4-induced immunosuppressive effect on antibody production seemed to be determined in part by the preexisting T cell repertoire, as was suggested by the recovery of responsiveness to the highly immunogenic antigen KLH and the transient inhibitory effect of anti-L3T4 treatment in primed animals. The regenerating L3T4+ T cell subpopulation was relatively incompetent in initiating B cell responses. More than 40% of the L3T4+ T cell compartment had to recover to provide help for the production of anti- KLH antibodies, whereas elimination of 90% of the L3T4+ helper cells did not inhibit a primary anti-KLH response. Evidence for a heterogeneous composition of the L3T4+ subset came from experiments using rIL-2 in vivo. The addition of rIL-2 during early helper cell depletion improved the recovery of the humoral responsiveness without apparently affecting the kinetics of the regeneration of L3T4+ T cells. Interestingly, humoral unresponsiveness to the weakly immunogenic antigen SpWMb persisted for at least 120 d. This long lasting unresponsiveness could not be explained by clonal depletion, and suggested as one possibility that the presence of antigen during regeneration of the L3T4+ helper cell population may have influenced the ultimate T cell repertoire.