Clonal expansion and TCR-independent differentiation shape the HIV-specific CD8+ effector-memory T-cell repertoire in vivo.
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.
Meyer-Olson
Dirk
D
Klinik für Immunologie und Rheumatologie, Medizinische Hochschule Hannover, Hanover, Germany. meyer.dirk@mh-hannover.de
Simons
Brenna C
BC
Conrad
Joseph A
JA
Smith
Rita M
RM
Barnett
Louise
L
Lorey
Shelly L
SL
Duncan
Coley B
CB
Ramalingam
Ramesh
R
Kalams
Spyros A
SA
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
C515370:CCR7 protein, human; D018959:CD57 Antigens; D011948:Receptors, Antigen, T-Cell; D054400:Receptors, CCR7; D017493:Leukocyte Common Antigens