Generation of CD3+CD8low thymocytes in the HIV type 1-infected thymus.
Infection with the HIV type 1 (HIV-1) can result both in depletion of CD4(+) T cells and in the generation of dysfunctional CD8(+) T cells. In HIV-1-infected children, repopulation of the peripheral T cell pool is mediated by the thymus, which is itself susceptible to HIV-1 infection. Previous work has shown that MHC class I (MHC I) molecules are strongly up-regulated as result of IFN-alpha secretion in the HIV-1-infected thymus. We demonstrate in this study that increased MHC I up-regulation on thymic epithelial cells and double-positive CD3(-/int)CD4(+)CD8(+) thymocytes correlates with the generation of mature single-positive CD4(-)CD8(+) thymocytes that have low expression of CD8. Treatment of HIV-1-infected thymus with highly active antiretroviral therapy normalizes MHC I expression and surface CD8 expression on such CD4(-)CD8(+) thymocytes. In pediatric patients with possible HIV-1 infection of the thymus, a low CD3 percentage in the peripheral circulation is also associated with a CD8(low) phenotype on circulating CD3(+)CD8(+) T cells. Furthermore, CD8(low) peripheral T cells from these HIV-1(+) pediatric patients are less responsive to stimulation by Ags from CMV. These data indicate that IFN-alpha-mediated MHC I up-regulation on thymic epithelial cells may lead to high avidity interactions with developing double-positive thymocytes and drive the selection of dysfunctional CD3(+)CD8(low) T cells. We suggest that this HIV-1-initiated selection process may contribute to the generation of dysfunctional CD8(+) T cells in HIV-1-infected patients.
Biomedical Sciences Graduate Program, University of California, San Francisco 94143, USA.
Mary E
ME
Keir
Michael G
MG
Rosenberg
Johan K
JK
Sandberg
Kimberly A
KA
Jordan
Andrew
A
Wiznia
Douglas F
DF
Nixon
Cheryl A
CA
Stoddart
Joseph M
JM
McCune
D017252:CD3 Complex / Q000096:biosynthesis*; D016827:CD8 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D005260:Female; D005333:Fetus; D015658:HIV Infections / Q000276:immunology / Q000473:pathology; D015497:HIV-1 / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D008297:Male; D009924:Organ Culture Techniques; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D015854:Up-Regulation / Q000276:immunology
D017252:CD3 Complex; D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D016898:Interferon-alpha