Studies in B cell-deficient mice generated by continuous injection of anti-μ antibodies (μSM) showed that T cell priming in lymph nodes was dependent on antigen presentation by B cells. This concept has recently become controversial since a wide range, from complete deficiency to near normal T cell responses, was reported in studies carried out with B cell-deficient mice generated by gene disruption (μMT). In this study we show that in the absence of B cells, T cell responses are greatly reduced in all the available μMT mouse strains although responses in μMT of the C57BL/6 background (which were used for most studies with μMT) were much more variable and could reach up to 42% of control. In contrast, T cell responses in μMT → F₁ bone marrow chimeras which have the same phenotype as μMT were totally impaired, suggesting a principle difference between mice developing without B cells (μMT mice) and μSM which are made B cell deficient only after birth. Normal T cell priming was completely restored by reconstitution of μMT and μMT → F₁ mice with syngeneic B cells. Interestingly, only B cell populations containing antigen-specific B cells were capable of reconstituting T cell responses. Monoclonal B cells taken from Ig transgenic mice could not reconstitute responses to an irrelevant antigen. We also found that B cells were also required for systemic T cell priming when antigen concentrations were limiting but were not required for priming (for T cell help) when mice were immunized with a high antigen dose.