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 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.
Integrated Department of Immunology, School of Medicine, University of Colorado Health Sciences Center, Denver, USA.
Julie A
JA
Lang
Douglas
D
Kominski
Donald
D
Bellgrau
Robert I
RI
Scheinman
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D015536:Down-Regulation; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000502:physiology*; D006706:Homeostasis; D019041:L-Selectin / Q000032:analysis; D008213:Lymphocyte Activation; D051381:Rats; D011916:Rats, Inbred F344; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*
D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell; D019041:L-Selectin