Death by Granzyme B

RESEARCH HIGHLIGHTS

APOPTOSIS Death by granzyme B DOI: 10.1038/nri1951 The death of effector T cells following pro-apoptotic ligands and effector lysosomal-associated membrane pro- Link activation is an important process molecules in AICD of T 1 cells and tein 1 (LAMP1; a marker of granules) Granzyme B H http://www.ncbi.nlm.nih.gov/ in the termination of an immune TH2 cells. Blocking the pro-apoptotic was observed in both resting TH1 entrez/viewer.fcgi?db=protein response. However, the mechanisms molecule CD95 ligand (also known cells and resting TH2 cells. However, &val=1247451 that are involved in this activation- as FAS ligand) with specific agents following TCR engagement, colocali-

induced cell death (AICD) through inhibited AICD of TH1 cells, as previ- zation was observed only in TH1 cells, engagement of the T-cell receptor ously reported. However, these agents indicating that granzyme B is released

(TCR) are not well understood. Now, had no effect on the death of TH2 from the granules on activation of TH2

new research published in Immunity cells. Similarly, blocking the activity of cells but not TH1 cells. Interestingly,

shows that granzyme B has an impor- several caspases affected only TH1-cell the amount of SPI6, which is a

tant role in AICD of T helper 2 (TH2) death, whereas inhibition of TRAIL protease inhibitor that specifically cells. (tumour-necrosis-factor-related inhibits the activity of granzyme B, Examination of the kinetics of apoptosis-inducing ligand) did not was found to be increased in activated

AICD, by staining for annexin V affect either cell type. Therefore, none TH1 cells but not activated TH2 cells.

and assessing membrane perme- of the classic pro-apoptotic pathways Therefore, in contrast to TH2 cells,

ability to propidium iodide, showed seems to be involved in the death of TH1 cells do not release granzyme B

that the death of TH1 cells occurred TH2 cells. from their granules, and they express a

more rapidly than that of TH2 cells Granzyme B is a serine protease protein that might protect them from following TCR engagement. This that is an important mediator of granzyme-B-mediated AICD. finding indicates that AICD is likely to target-cell apoptosis by cells such as Following restimulation in vitro, involve different mechanisms in these natural killer cells and cytotoxic CD8+ CD4+ T cells from granzyme-B-defi- two cell populations. Therefore, the T cells. However, granzyme B has also cient mice that had been immunized authors examined the role of several been shown to exert its function on with ovalbumin formulated in alum

certain cells that produce it, indicating produced large amounts of the TH2 that it might be involved in AICD. cytokines interleukin-4 (IL-4), IL-5 Interestingly, Devadas and colleagues and IL-13, but interferon-γ was showed that inhibition of granzyme B undetectable. In a mouse model of

blocked AICD of TH2 cells but not ovalbumin-induced allergic lung

TH1 cells. Cells that were isolated inflammation, which depends on a

from granzyme-B-deficient mice TH2-cell response, mice deficient in

and cultured in TH2-cell-polarizing granzyme B had considerably more conditions before activation showed a cellular infiltrate in the lungs and similar resistance to AICD. more IL-4 and IL-5 in bronchoalveo-

So why are TH2 cells, but not TH1 lar-lavage fluid than did granzyme-B- cells, sensitive to granzyme-B-medi- sufficient (control) mice. ated AICD? Using northern-blotting So the data show that granzyme B

analysis and real-time PCR, the is crucial for AICD of TH2 cells but not

authors determined that resting and TH1 cells and might therefore have a

activated TH1 cells and activated TH2 role in regulating TH2-cell responses cells express large amounts of this in vivo. protease, indicating that the sensitivity Olive Leavy

of TH2 cells to granzyme-B-mediated apoptosis is not due to preferential ORIGINAL RESEARCH PAPER Devadas, S. et al. Granzyme B is critical for T cell receptor-induced expression of granzyme B. The cell death of type 2 helper T cells. Immunity 25, authors then examined the release 237–247 (2006) of granzyme B by degranulation. Colocalization of granzyme B with