CD4 and CD8 T cell immune activation during chronic HIV infection: roles of homeostasis, HIV, type I IFN, and IL-7.
Immune activation plays an important role in the pathogenesis of HIV disease. Although the causes are not fully understood, the forces that lead to immune dysfunction differ for CD4 and CD8 T cells. In this study, we report that the molecular pathways that drive immune activation during chronic HIV infection are influenced by differences in the homeostatic regulation of the CD4 and CD8 T cell pools. Proliferation of CD4 T cells is controlled more tightly by CD4 T cell numbers than is CD8 T cell proliferation. This difference reflects the importance of maintaining a polyclonal CD4 T cell pool in host surveillance. Both pools of T cells were found to be driven by viral load and its associated state of inflammation. In the setting of HIV-induced lymphopenia, naive CD4 T cells were recruited mainly into the proliferating pool in response to CD4 T cell depletion, whereas naive CD8 T cell proliferation was driven mainly by levels of HIV RNA. RNA analysis revealed increased expression of genes associated with type I IFN and common γ chain cytokine signaling in CD4 T cell subsets and only type I IFN-associated genes in CD8 T cell subsets. In vitro studies demonstrated enhanced STAT1 phosphorylation in response to IFN-α and increased expression of the IFNAR1 transcripts in naive and memory CD4 T cells compared with that observed in CD8 T cells. CD4 T cell subsets also showed enhanced STAT1 phosphorylation in response to exogenous IL-7.
Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. catalfam@mail.nih.gov
Marta
M
Catalfamo
Christopher
C
Wilhelm
Lueng
L
Tcheung
Michael
M
Proschan
Travis
T
Friesen
Jung-Hyun
JH
Park
Joseph
J
Adelsberger
Michael
M
Baseler
Frank
F
Maldarelli
Richard
R
Davey
Gregg
G
Roby
Catherine
C
Rehm
Clifford
C
Lane
D000328:Adult; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D049109:Cell Proliferation; D002908:Chronic Disease; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000502:physiology*; D016898:Interferon-alpha / Q000502:physiology; D015851:Interleukin-7 / Q000494:pharmacology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008231:Lymphopenia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000276:immunology; D012367:RNA, Viral / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D019562:Viral Load / Q000276:immunology
C508605:IL7 protein, human; D007370:Interferon Type I; D016898:Interferon-alpha; D015851:Interleukin-7; D012367:RNA, Viral; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human
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