Although normal numbers of CD4+ T cells are present in the human neonate, cord blood CD4+ cells are deficient in their ability to provide help for antibody production. In the present studies, we have examined the cellular basis for this functional deficit by analyzing the phenotypic properties and immunoregulatory functions of the subsets of cord blood CD4+ cells defined by anti-CD45RA mAb. In contrast to CD4+ cells from adults, greater than 90% of cord blood CD4+ cells expressed the CD45RA, CD38, and Leu-8 membrane Ag. When neonatal CD4+ cells were cultured with adult B cells and PWM or anti-CD4+ mAb, no helper function was apparent. However, when the small number of CD4+CD45RA- cells in cord blood were purified and similarly analyzed, helper activity comparable to that of adult CD4+CD45RA- cells was found. This helper function was profoundly suppressed by the presence of even small numbers of cord blood (but not adult) CD4+CD45RA+ cells. Irradiation of mitomycin C treatment of neonatal CD4+CD45RA+ cells abrogated their suppressor activity, but did not induce helper capability. However, after activation with PHA and culture in IL-2, cord blood CD4+CD45RA+ cells lost their suppressor activity and acquired the ability to provide help for B cell differentiation. This functional maturation was accompanied by their conversion to the CD4+CD45RA- phenotype. Thus, whereas cord blood CD4+CD45RA+ and CD4+CD45RA- cells share certain properties with the analogous subsets in adults, our data show that the dominant immunoregulatory function of cord blood CD4+ cells is suppression mediated by CD4+CD45RA+ (and CD38+) cells. In view of these phenotypic and functional differences between neonatal and adult CD4+CD45RA+ cells, we propose that "naive" CD4+CD45RA+ cells undergo age-related maturational changes that are unrelated to their postulated activation-dependent post-thymic differentiation into CD4+CD45RA- "memory" cells capable of helper functions.