| First Author | Brenner D | Year | 2007 |
| Journal | Blood | Volume | 110 |
| Issue | 12 | Pages | 3968-77 |
| PubMed ID | 17712048 | Mgi Jnum | J:149104 |
| Mgi Id | MGI:3847612 | Doi | 10.1182/blood-2007-01-071167 |
| Citation | Brenner D, et al. (2007) Caspase-cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes. Blood 110(12):3968-77 |
| abstractText | Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-kappaB activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-kappaB and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2-driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C selectively blocks induction of NF-kappaB-dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim. Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C-dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes. |
