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

Publisher Website
Google Scholar
Abstract
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.