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The Role of Apoptosis in the Resistance of DRAK2‐Deficient Mice to Autoimmunity
Author(s) -
Hernandez Jeniffer B.,
Ramos Stephanie J.,
Gatzka Martina,
Walsh Craig M.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.669.7
Subject(s) - il 2 receptor , experimental autoimmune encephalomyelitis , biology , cytotoxic t cell , autoimmunity , effector , microbiology and biotechnology , t cell , immunology , peripheral tolerance , cancer research , immune system , in vitro , genetics
Autoimmune disease often occurs via the escape of autoreactive T cells from apoptosis, implying a breakdown of central or peripheral tolerance mechanisms. We have recently demonstrated that thymocytes and T cells lacking the serine/threonine kinase DRAK2 have a diminished activation threshold, suggesting that this kinase serves as a quiescence factor to maintain tolerance to weak self‐antigens. Drak2 − / − T cells produce higher levels of the cytokine IL‐2 and exhibit enhanced sensitivity to TCR mediated stimulation. Surprisingly, Drak2 − / − mice are resistant to experimental autoimmune encephalomyelitis (EAE). EAE is a disease induced in mice by immunization with MOG 35–55 peptide, which elicits multiple sclerosis‐like symptoms due to T cell activation and recruitment into the CNS. We have observed enhanced apoptosis in effector T cells derived from Drak2 − / − mice, suggesting that DRAK2 serves as both a quiescence factor in naïve T cells and a survival factor in effector T cells. T cells from MOG 35–55 ‐immunized DRAK2‐deficient mice have decreased levels of interferon gamma, IL‐17, and increased regulatory T cells (Treg) compared to wild‐type mice. We hypothesize that the decrease in these cytokines and increase in Treg is due to the increase in apoptosis of the effector cells. In accord with this, sensitivity to MOG 35–55 peptide induced EAE was rescued in DRAK2 − / − mice by a T cell‐specific Bcl‐ xL transgene, demonstrating that the resistance to this disease is a consequence of defective survival of MOG‐specific T cells. These results highlight the potential for inhibiting autoimmunity without affecting anti‐pathogen responsiveness via DRAK2 blockade. This work was supported by NIH grant R01 AI063419.