Cytotoxic T cells play a critical role in the control of HIV and the progression of infected individuals to AIDS. 2B4 (CD244) is a member of the SLAM family of receptors that regulate lymphocyte development and function. The expression of 2B4 on CD8(+) T cells was shown to increase during AIDS disease progression. However, the functional role of 2B4(+) CD8(+) T cells against HIV infection is not known. Here, we have examined the functional role of 2B4(+) CD8(+) T cells during and after stimulation with HLA B14 or B27 restricted HIV epitopes. Interestingly, IFN-gamma secretion and cytotoxic activity of 2B4(+) CD8(+) T cells stimulated with HIV peptides were significantly decreased when compared to influenza peptide stimulated 2B4(+) CD8(+) T cells. The expression of the signaling adaptor molecule SAP was downregulated in 2B4(+) CD8(+) T cells upon HIV peptide stimulation. These results suggest that 2B4(+) CD8(+) T cells play an inhibitory role against constrained HIV epitopes underlying the inability to control the virus during disease progression. Published by Elsevier Inc.