Partial activation precedes apoptotic death in T cells harboring an IAN gene mutation

The Biobreeding diabetes‐prone rat suffers from a profound peripheral lymphopenia and yet succumbs to a T cell‐dependent autoimmune disease. Lymphopenia segregates with a mutated chromosomal locus, termed lyp, recently identified as a frameshift mutation in IAN4. Others have correlated loss of IAN4...

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Published inEuropean Journal of Immunology Vol. 34; no. 9; pp. 2396 - 2406
Main Authors Lang, Julie A., Kominski, Douglas, Bellgrau, Donald, Scheinman, Robert I.
Format Journal Article
LanguageEnglish
Published Weinheim WILEY‐VCH Verlag 01.09.2004
Subjects
Animals
Apoptosis
Cells, Cultured
Cellular activation
Diabetes
Down-Regulation
Histocompatibility Antigens Class II - genetics
Histocompatibility Antigens Class II - physiology
Homeostasis
L-Selectin - analysis
Lymphocyte Activation
Rats
Rats, Inbred F344
Receptors, Antigen, T-Cell - physiology
T lymphocytes
T-Lymphocytes - immunology
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Summary:The Biobreeding diabetes‐prone rat suffers from a profound peripheral lymphopenia and yet succumbs to a T cell‐dependent autoimmune disease. Lymphopenia segregates with a mutated chromosomal locus, termed lyp, recently identified as a frameshift mutation in IAN4. Others have correlated loss of IAN4 function with decreased mitochondrial integrity resulting in T cell apoptosis. Here we report that IAN4–/– T cells enter a state similar to that of partial activation wherein they down‐regulate CD62L and undergo incomplete blasting yet do not progress through mitosis. When given a strong stimulus, this partial activation phenotype can be overcome. This phenotype can be recapitulated in wild‐type T cells through suboptimal stimulation. The phenotype is not simply a reaction to the lymphopenic environment, as spontaneous CD62L down‐regulation occurs in mature single‐positive medullary thymocytes that develop within a non‐lymphopenic environment, and normal T cells do not undergo similar blasting when parked in a lymphopenic environment. Finally, we show that IAN4–/– T cells are more readily triggered via TCR stimulation. Thus, in addition to their role in apoptosis, IAN family members may also play a role in regulating the T cell activation state through modulation of TCR signaling strength.
Bibliography:The last two authors contributed equally to this work.
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ISSN:0014-2980
1521-4141
1365-2567
DOI:10.1002/eji.200324751