Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1α-deficient chimeric mice

Abstract

Immune cells are exposed to low oxygen tensions as they develop and migrate between blood and different tissues, but the mechanisms by which lymphocytes adapt to hypoxia are poorly understood. Studies reported here of hypoxia-inducible factor 1␣ (HIF-1␣) in lymphocyte development and functions suggest that it has a critical role in regulation of these processes. HIF-1␣ deficiency in Hif1␣ ؊/؊ 3 Rag2 ؊/؊ chimeric mice results in dramatic and cell lineage-specific defects, which include appearance of abnormal peritoneal B-1-like lymphocytes, with high expression of B220 (CD45) receptor-associated protein tyrosine phosphatase and autoimmunity (accumulation of anti-dsDNA antibodies and rheumatoid factor in serum, deposits of IgG and IgM in kidney and proteinuria) as well as distortions of maturation of B-2 lymphocytes in bone marrow.

Cutting Edge: Hypoxia-Inducible Factor 1α and Its Activation-Inducible Short Isoform I.1 Negatively Regulate Functions of CD4+ and CD8+ T Lymphocytes

“…Mice that were HIF-1␣-floxed and heterozygous for Lck-Cre had HIF-1␣-deficient T cells, whereas control wild-type mice were their Lck-Cre-negative/HIF-1␣-floxed siblings. Chimeric mice with lymphocyte-specific deletion of HIF-1␣ were described previously (8).…”

“…Accordingly, we have proposed that changes in levels of HIF-1␣ may play not only the energy-providing but also a regulatory role in T cell functions in inflamed and hypoxic tissue microenvironments (2). This proposal was prompted by our earlier observations of increased inflammatory tissue damage in chimeric mice with complete HIF-1␣ deletion in cells of adaptive immune system (8). These observations suggested that HIF-1␣ in T cells may play the anti-inflammatory and tissue-protecting role by negatively regulating T cell functions (2, 9, 10).…”

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

“…The HIF1a/ARNT dimer activates transcription through the hypoxia response element (HRE: TACGTG) in the promoter or enhancer region of target genes that include vascular endothelial growth factor (VEGF), erythropoietin and phosphoglycerate kinase (PGK). In mammals, HIF1 is required for the establishment and utilization of the placenta, cartilage, erythroid, vascular, cardiac and respiratory systems (Maltepe et al, 1997;Iyer et al, 1998;Ryan et al, 1998;Kotch et al, 1999;Kline et al, 2002;Kojima et al, 2002;Ramirez-Bergeron et al, 2004). In keeping with this fundamental role in normal development, HIF1 activity has also been associated with human diseases.…”

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

“…Thus, by increasing the NK cell cytotoxicity and IL-12 serum level from stimulated NK cells, this A 3 agonist decreased the growth and proliferation of B16-F10 melanoma cells [146]. Hoskin et al have also shown that 2-CADO inhibits the MHC-unrestricted cytolytic activity of anti-CD3-activated killer cells, thus suppressing the antitumor immune response [242]. Therefore, adenosine modulates the protective effect of innate immune cells (i.e., macrophages, DCs, and NK cells) towards their cancer-promoting phenotype leading to survival, growth, and development of tumor mass.…”

“…Thus, adenosine and hypoxia both lead to immunosuppression during inflammation and tumor pathogenesis. In addition to this, HIF-1α-deficient chimeric mice develop abnormal B lymphocyte development (i.e., appearance of abnormal peritoneal B-1-like lymphocytes, with high expression of B220 (CD45) receptorassociated protein tyrosine phosphatase) and autoimmunity (i.e., anti-dsDNA antibodies and rheumatoid factor in serum, deposits of IgG and IgM in kidney and proteinuria as well as distortions of maturation of B-2 lymphocytes in bone marrow) [242]. In addition to this, T cell-specific deletion of HIF-1α in mice prevented them from acquiring sepsis and led to exaggerated proinflammatory immune response required to clear bacteria efficiently from circulation and increased their survival; these elevated HIF-1α levels may lead to immunosuppression [243].…”