Journal
BLOOD
Volume 116, Issue 3, Pages 396-405Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-11-254136
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Funding
- Bundesministerium fur Bildung und Forschung/Kompetenznetz HIV [DMO/01Kl0501]
- Helmholtz-Zentrum fur Infektionsforschung [DMO/IG-SCID-TwinPro-02]
- European AIDS Treatment Network NEAT [DMO/WP3]
- National Institutes of Health [SAK R01AI39966]
- Vanderbilt-Meharry Center for AIDS Research Immunopathogenesis Core Facility [2P30AI054999]
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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. (Blood. 2010; 116(3): 396-405)
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