A small subpopulation of CD4(+) T cells found in peripheral blood coexpresses the CD57(+) marker normally found on, e.g., NK cells. It is known that this population occurs in a higher frequency in certain diseases, The same antigen has also been shown to be expressed on CD4(+) T cells derived from germinal centers, The localization of this cell population to specialized lymphoid structures suggests that it may play a role in the evolution of the antibody response following antigenic stimulation in vivo. We have examined the ability of peripheral blood helper T cells coexpressing CD57 to participate in B cell activation/differentiation and evaluated their responses to polyclonal stimulation. The CD4(+)CD57(+) T cells do not express mRNA for a number of different cytokines or for the CD40 ligand after activation in vitro. Furthermore these cells do not induce differentiation of B cells into immunoglobulin-producing cells. Consequently, despite their CD4 phenotype and their ability to be activated, to express the IL-2 receptor, and to enter into the cell cycle, they do not act as T helper cells under conditions where CD4(+)/CD57(-) cells normally do so. The findings suggest that this peripheral blood helper T cell population is functionally different from regular CD4(+) T cells. The basis for the lack of proper costimulatory signals for immunoglobulin production might be related to the low expression of CD28. (C) 1995 Academic Press, Inc.