Functionally impaired HIV-specific CD8 T cells show high affinity TCR-ligand interactions.
We eventually isolated two different clonotypic CD8 T cell subsets recognizing an HIV Pol-derived epitope peptide (IPLTEEAEL) in association with HLA-B35 from a chronic HIV-infected patient. By kinetic analysis experiments, the subsets showed a >3-fold difference in half-lives for the HLA tetramer in complex with the Pol peptide. In functional assays in vitro and ex vivo, both subsets showed substantial functional avidity toward peptide-loaded cells. However, the high affinity subset did not show cytolytic activity, cytokine production, or proliferation activity toward HIV-infected cells, whereas the moderate affinity one showed potent activities. Furthermore, using ectopic expression of each of the TCR genes into primary human CD8 T cells, the CD8 T cells transduced with the high affinity TCR showed greater binding activity toward the tetramer and impaired cytotoxic activity toward HIV-infected cells, corroborating the results obtained with parental CD8 T cells. Taken together, these data indicate that impaired responsiveness of T cells toward HIV-infected cells can occur at the level of TCR-ligand interactions, providing us further insight into the immune evasion mechanisms by HIV.
Ueno
Takamasa
T
Division of Viral Immunology, Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
Tomiyama
Hiroko
H
Fujiwara
Mamoru
M
Oka
Shinichi
S
Takiguchi
Masafumi
M
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D002999:Clone Cells; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D015684:Gene Products, pol / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D019673:Genes, T-Cell Receptor alpha; D019674:Genes, T-Cell Receptor beta; D006678:HIV / Q000276:immunology*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism / Q000821:virology; D014161:Transduction, Genetic
D018984:Epitopes, T-Lymphocyte; D015684:Gene Products, pol; D008024:Ligands; D016693:Receptors, Antigen, T-Cell, alpha-beta