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The primary in vitro IgM response to the major histocompatibility (MHC) antigens expressed on chicken red blood cells (CRBC) has been shown to critically depend on the cooperation between antigen-specific helper factor from CRBC-primed thymus-derived helper (T) cells, bone marrow-derived (B) cells, and radioresistant (A) cells. A 500- to 1000-fold enrichment for immunocompetent B cells by means of a rosette technique permitted the culturing of as few as 2000 B cells that yielded on the average 500 plaque-forming cells against CRBC within 3 days of culture. Cell reconstitution experiments clearly showed that the presence of A cells can be circumvented by an A cell-derived secretory product. This is in disagreement with the hypothesis that helper factor acts as a mediator for antigen presentation on the A cell surface membrane. The spectrum of helper factor cross-reactivity with respect to certain alleles of the B locus was found comparable to that of antibody.