Infection with encapsulated bacteria can be prevented by vaccination with capsular polysaccharides, either plain or conjugated to a protein carrier. However, results concerning these vaccinations raise several paradoxes. Polysaccharides from encapsulated bacteria are generally considered to be T cell-independent antigens which are unable to trigger a T cell-dependent germinal center reaction, but, strikingly, anti-polysaccharide antibodies are often mutated in humans. Polysaccharide–protein conjugate vaccines are able to induce a true T cell-dependent memory response with a rise in antibody titers and a switch to high-affinity IgG antibodies in children below two years of age, but neither the plain nor the conjugated vaccine can induce memory in older infants and adults. We propose some explanations for these paradoxes based on our recent observation that humans display a circulating splenic marginal zone B-cell population with a pre-diversified immunoglobulin repertoire in charge of the immune response to T cell-independent antigens. Infection with encapsulated bacteria can be prevented by vaccination with capsular polysaccharides, either plain or conjugated to a protein carrier. However, results concerning these vaccinations raise several paradoxes. Polysaccharides from encapsulated bacteria are generally considered to be T cell-independent antigens which are unable to trigger a T cell-dependent germinal center reaction, but, strikingly, anti-polysaccharide antibodies are often mutated in humans. Polysaccharide–protein conjugate vaccines are able to induce a true T cell-dependent memory response with a rise in antibody titers and a switch to high-affinity IgG antibodies in children below two years of age, but neither the plain nor the conjugated vaccine can induce memory in older infants and adults. We propose some explanations for these paradoxes based on our recent observation that humans display a circulating splenic marginal zone B-cell population with a pre-diversified immunoglobulin repertoire in charge of the immune response to T cell-independent antigens. An antigen that can induce an antibody response without the help of Th cells. Bacterial capsular polysaccharides are TI antigens. An antigen that requires interaction between Th cells and B cells to induce an antibody response. Most protein antigens are T-dependent. T-dependent responses take place in germinal centers. Mutations occurring with high frequency in the variable (V) regions of rearranged immunoglobulin (Ig) genes. In most mammalian species, hypermutation is used for the generation of high-affinity antibodies in response to td antigens. It can also be used as a diversification process (e.g. in sheep) to generate the pre-immune antibody repertoire. The process whereby IgM+ B cells switch, after antigen encounter, to the expression of a different isotype (or class, e.g. IgG, IgA or IgE) by replacing its Ig heavy chain constant region gene. Specialized structures that form transiently in secondary lymphoid organs (e.g. spleen, lymph nodes) during immune responses to TD antigens. Hypermutation, isotype switch, affinity maturation and memory B cell formation take place within these structures. Refers to the increase in the affinity of antibodies produced during the course of T cell-dependent responses. This process results from the selection within germinal centers of B cells harboring mutated receptors with higher affinity for the antigen. A B lymphocyte that has been stimulated by a TD antigen, and has differentiated into a class-switched, long-lived, non-secreting B cell-carrying mutated Ig. Memory B cells, when re-exposed to the immunizing antigen, are responsible for generating faster responses with higher affinity. A primary immunodeficiency characterized by normal or increased serum IgM levels and low or absent IgG, IgA and IgE serum levels, owing to a defect in isotype switch.