Cutting edge: hypoxia-inducible factor 1alpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+ and CD8+ T lymphocytes.
To evaluate the role of hypoxia-inducible factor 1alpha (HIF-1alpha) and its TCR activation-inducible short isoform I.1 in T cell functions, we genetically engineered unique mice with: 1) knockout of I.1 isoform of HIF-1alpha; 2) T cell-targeted HIF-1alpha knockdown; and 3) chimeric mice with HIF-1alpha gene deletion in T and B lymphocytes. In all three types of mice, the HIF-1alpha-deficient T lymphocytes, which were TCR-activated in vitro, produced more proinflammatory cytokines compared with HIF-1alpha-expressing control T cells. Surprisingly, deletion of the I.1 isoform, which represents < 30% of total HIF-1alpha mRNA in activated T cells, was sufficient to markedly enhance TCR-triggered cytokine secretion. These data suggest that HIF-1alpha not only plays a critical role in oxygen homeostasis but also may serve as a negative regulator of T cells.
Lukashev
Dmitriy
D
New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115, USA.
Klebanov
Boris
B
Kojima
Hidefumi
H
Grinberg
Alex
A
Ohta
Akiko
A
Berenfeld
Ludmilla
L
Wenger
Roland H
RH
Ohta
Akio
A
Sitkovsky
Michail
M
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000502:physiology; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell / Q000502:physiology
D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020033:Protein Isoforms; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell