Caspase-cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes

Abstract

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-κB activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-κB 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 se-lectively blocks induction of NF-κB–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.

Germinal center kinases in immune regulation

“…[6][7][8][9] The adhesion and degranulation promoting adaptor protein (ADAP) forms a complex with Src kinase-associated phosphoprotein 55 kD (SKAP55) and Ras-associated protein 1 (Rap1)-GTP-interacting adaptor molecule (RIAM). ADAP binds to SLP-76 in a TCR-stimulation dependent manner to translocate the ADAP-SKAP55-RIAM complex to the cell membrane and further recruit the active small GTPase Rap1.…”

The granzyme B-Serpinb9 axis controls the fate of lymphocytes after lysosomal stress

“…The best studied is the extrinsic, cell death receptor-dependent pathway, 2 although death receptor-independent pathways also exist. 3,4 Activated natural killer (NK) cells are also eliminated via death receptor signalling. However, in some NK cells restimulation of activating receptors such as CD94, 5 CD2 6 or CD16 5,7,8 results in very rapid death, independent of death receptor signalling.…”

Vesicles Released by Activated T Cells Induce Both Fas-Mediated RIP-Dependent Apoptotic and Fas-Independent Nonapoptotic Cell Deaths

“…The involvement of FasL-Fas-mediated killing has also been evident in CSup-induced cell death. Experiments using long-term (at least 18-h) cell cultures have shown that AICD of T cells may occur in both a Fas-dependent (1-3) and Fas-independent manner (4)(5)(6)(7)(8)50).…”