title: Clonal expansion and TCR-independent differentiation shape the HIV-specific CD8+ effector-memory T-cell repertoire in vivo.
abstract: Flexibility of the HIV-specific T-cell receptor repertoire is a hallmark of HIV-1 infection. Altered differentiation of HIV-specific CD45RO(+)/CCR7(-) (TemRO) CD8(+) effector-memory T cells into CD45RA(+)/CCR7(-) (TemRA) CD8(+) effector-memory T cells as well as increased expression of the senescence marker CD57 has been frequently observed HIV-1 infection, but the structural relationship between clonal expansion and T-cell differentiation has not been defined. In this study, we demonstrate that HIV-specific clonotypes have differing degrees of TemRA differentiation but always maintain a significant proportion of TemRO-phenotype cells. These data indicate that structural constraints of the TCR/peptide major histocompatibility complex interaction play a central role in the TemRA differentiation of HIV-specific CD8(+) T cells in chronic HIV-1 infection. Clonotypes with a predominantly TemRA phenotype had a substantial fraction of cells without expression of CD57; and in contrast to the high clonotypic variability of TemRA differentiation, expression of CD57 was highly correlated among T-cell clonotypes within epitope-specific responses, indicating TCR-independent expression of CD57 in vivo. Our data highlight the importance of the structural composition of the TCR repertoire for the effector-memory differentiation of the immune response in chronic viral infections and suggest that TCR-dependent and -independent homeostasis shapes the pathogen-specific effector-memory repertoire in vivo.
authors.affiliation: Klinik für Immunologie und Rheumatologie, Medizinische Hochschule Hannover, Hanover, Germany. meyer.dirk@mh-hannover.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Meyer-Olson
authors.forename: Brenna C
authors.initials: BC
authors.lastname: Simons
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Conrad
authors.forename: Rita M
authors.initials: RM
authors.lastname: Smith
authors.forename: Louise
authors.initials: L
authors.lastname: Barnett
authors.forename: Shelly L
authors.initials: SL
authors.lastname: Lorey
authors.forename: Coley B
authors.initials: CB
authors.lastname: Duncan
authors.forename: Ramesh
authors.initials: R
authors.lastname: Ramalingam
authors.forename: Spyros A
authors.initials: SA
authors.lastname: Kalams
mesh_terms: D000595:Amino Acid Sequence; D018959:CD57 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D002454:Cell Differentiation / Q000276:immunology; D002999:Clone Cells / Q000276:immunology / Q000473:pathology; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology; D015497:HIV-1; D006801:Humans; D007156:Immunologic Memory; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008969:Molecular Sequence Data; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D054400:Receptors, CCR7 / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology
chemical_list: C515370:CCR7 protein, human; D018959:CD57 Antigens; D011948:Receptors, Antigen, T-Cell; D054400:Receptors, CCR7; D017493:Leukocyte Common Antigens