Heat shock proteins (HSP) can interact with a wide variety of peptides and the resulting HSP:peptide complexes are known to be highly immunogenic. The ability of HSP:peptide complexes to elicit CD8 + T cell responses by cross-presentation of exogenous antigen via MHC class I is well known. In contrast, their role in the activation of CD4 + T cells is less clearly defined, although several recent studies in mice and T cell lines suggest an involvement of HSP in the presentation of antigenic peptides via MHC class II. In this study we have investigated the potential of antigenic peptides from tetanus toxin and influenza hemagglutinin complexed to the human stress-inducible Hsp70 to enhance activation and proliferation of human memory CD4 + T cells. Hsp70:peptide complexes were found to amplify the proliferation of antigen-specific CD4 + T cells as confirmed by HLA-DR tetramer staining. Complex formation of the antigenic peptide with Hsp70 was absolutely required to elicit an antigen-specific amplification. This effect was most pronounced at low doses of antigen and decreasing APC/CD4 + T cell ratios. Taken together, we show the potential of Hsp70 to enhance antigen-specific CD4 + T cell proliferation and to increase the immunogenicity of presented peptides in human CD4 + T cells.

When Wolbach and Howe (1) studied vitamin A-deficient rats in the Twenties, they noted among the many histopathologic changes a marked atrophy of the thymus and loss of lymphoid cells in spleen and lymph nodes. Subsequent observations revealed that avitaminotic birds develop deficient bursas (2), and that avitaminotic rats reared conventionally, as opposed to under germ-free conditions, suffer from multiple, life-threat, ming infections (3) . These findings may have signalled the pos sibility that lymphopoiesis is compromised in vitamin A deficiency, but a formal connection to the physiology of immune cells has not been established . Despite sporadic evidence in the literature (reviewed in references 4 and 5) that retinoids influence immune responses, to our knowledge systematic studies to uncover the mechanism underlying immune system enhancement have not been carried out .In the course of studies of a growth factor for human, EBV transformed B lymphocytes, we have isolated a lipid-like molecule by extraction of serum with organic solvents . We show in the present report that this low molecular weight factor consists of all-trans retinol . The finding that vitamin A supports the growth of cultured human B cells has not previously been reported . It may be related to growth stimulation of epithelial cell lines by retinoids although there are several reports to the contrary (for review, see reference 6), demonstrating growth inhibition by retinoids . We had previously isolated a protein on the basis of its ability to stimulate the proliferation of lymphoblastoid cells grown at low density (7) . The bioactivity of this protein was markedly enhanced by a lipid cofactor. We now know that the protein factor represents the monomer subunit of prealbumin (PA)' (unpublished results), and that the lipid cofactor is retinol . PA (8) is one of two protein molecules of a complex endowed with the task of transporting retinol in the blood, the other being retinol-binding protein (RBP) (9) . Retinol binds to RBP, conferring high binding affinity for PA

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