Dual mechanism of impairment of interleukin-7 (IL-7) responses in human immunodeficiency virus infection: decreased IL-7 binding and abnormal activation of the JAK/STAT5 pathway.
Interleukin-7 (IL-7) plays a central role in controlling the homeostasis of both naive and long-term-memory CD4(+) T cells. To better understand how human immunodeficiency virus (HIV) perturbs CD4(+) T-cell homeostasis, we performed a detailed analysis of IL-7R expression, IL-7 binding, and IL-7-dependent early and late signaling events in CD4(+) T-cell subsets from viremic and efficiently treated patients. HIV infection differentially affected the expression of IL-7 receptor (IL-7R) chains, with decreases in IL-7Ralpha/CD127 expression in the memory subset and increases in gammac/CD132 expression in all CD4(+) T cells. This resulted in preserved IL-7 binding in the naive compartment and decreased IL-7 binding in the memory compartment of viremic patients. Accordingly, the percentages of cells signaling in response to IL-7, as measured by pSTAT5 induction, were decreased in memory subsets, including conventional CD4(+) T cells and regulatory T cells. However, the levels of pSTAT5 induction per responding cell, as measured by pSTAT5 fluorescence intensity, were increased within all naive and memory CD4(+) T-cell subsets of viremic patients. The basal level of pSTAT5 was also increased, indicating a constitutive activation of the JAK/STAT5 pathway. IL-7 functional responses, as measured by Bcl-2, CD25, and Foxp3 induction, were impaired in viremic patient CD4(+) T cells, suggesting that chronic activation led to downstream defects in the STAT5 signaling pathway. Thus, HIV infection perturbs IL-7 responses at both receptor binding and signaling steps, which likely compromises the regenerative capacity of the CD4(+) T-cell pool and may contribute to CD4(+) T-cell depletion.
Juffroy
Olivier
O
Institut Pasteur, Unité d'Immunogénétique Cellulaire, 75724 Paris Cedex 15, France.
Bugault
Florence
F
Lambotte
Olivier
O
Landires
Ivan
I
Viard
Jean-Paul
JP
Niel
Loïc
L
Fontanet
Arnaud
A
Delfraissy
Jean-François
JF
Thèze
Jacques
J
Chakrabarti
Lisa A
LA
D000328:Adult; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology / Q000821:virology*; D016022:Case-Control Studies; D015658:HIV Infections / Q000276:immunology*; D006706:Homeostasis; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism*; D008875:Middle Aged; D011485:Protein Binding; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D019562:Viral Load
D015851:Interleukin-7; D050799:STAT5 Transcription Factor; D053612:Janus Kinases