Per aspera ad astra: from early T-cell development to accelerating late T-cell apoptosis

Comment on Schnell et al, page 591

A sophisticated hunt for genes differentially expressed during early T-cell development has led to the identification of Gimap4, a gene with a promising expression profile during T-cell development. However, gene-knockout reveals that Gimap4 does not play a role in T-cell development, selection, and activation, but that instead it acts as an accelerator of T-cell death during the final transition from a cell with apoptotic morphology to one with a disintegrated plasma membrane.

In this issue of Blood, Schnell and colleagues report on the identification of Gimap4, a protein that is differentially expressed during T-cell development, and its surprising function in programmed cell death. Gimap4 is a member of the GTPase of the immunity-associated protein (Gimap) family,¹  also known as the immune-associated nucleotide-binding (IAN) protein family.² 

The original aim of the study was to identify genes involved in early T lymphocyte development. To identify such genes, the Jacobs group applied a sophisticated screening approach: they performed differential display of mRNA from sorted subsets of thymocytes obtained from Rag2–deficient mice that had either been treated with anti-CD3ϵ or been left untreated.³  The analysis found that Gimap4 was one of the most prominently differentially expressed genes. The expression pattern of Gimap4 in early T-cell development also looked promising: while being induced in precursor T cells, Gimap4 expression was shut off during thymic-positive selection, but Gimap4 was re-expressed thereafter and, interestingly, remained expressed throughout T-cell life.

Because everything indicated that it would be worthwhile to generate Gimap4-deficient mice, Schnell and colleagues did so. Needless to say, the authors were not amused and were probably very disappointed to learn that Gimap4-deficient mice showed completely normal early T-cell development. They then submitted these mice to an extensive immunologic analysis, but again, no effect of Gimap4 knockout on T-cell development, selection, and activation could be detected. So did Jacobs' group end up identifying and then even knocking out a gene without a function in the immune system? Well, they did not give up at this point.

As mentioned, the authors had observed that Gimap4 remained expressed in mature peripheral T cells. Intriguingly, Gimap5 is the gene that is spontaneously mutated in the Bio-Breeding diabetes-prone (BB-DP) rat; this mutation is responsible for the severe lymphopenia (lyp mutation) and the development of insulin-dependent diabetes mellitus (iddm1 mutation) in these rats.^4,5  In addition, it had been shown that other Gimap family members can influence T-cell survival and proliferation.⁶  Consequently, Schnell et al examined whether apoptosis of peripheral T cells from Gimap4-deficient mice was normal. When they serum-starved splenic T cells from wild-type and Gimap4-deficient mice or treated them with etoposide, dexamethasone, or γ-irradation, Schnell et al consistently observed that the ratio of apoptotic to necrotic cells was about 4-fold higher in T cells from Gimap4-deficient mice than in controls. At the same time, the total number of dead cells and cells with activated caspase-3 were unaffected. Thus, Gimap4 acts as an accelerator for a late step in the cell death program; that is, at the transition from a late zeiotic or “blebbing” cell with an intact plasma membrane—an “apoptotic” cell—to a cell in which the plasma membrane is disintegrated—a “necrotic” cell.

It is currently not well understood how plasma membrane disintegration is achieved during cell death induction, let alone the functional consequences of a shift in the ratio of apoptotic to necrotic cells like that observed in this study. However, it is tempting to speculate that the induction of autoimmunity as well as the ability to mount an immune response against cancer cells may be affected by the ratio of apoptotic to necrotic cells and that a shift in this ratio might influence the immunologic outcome of cell death induction. It will be interesting to see how the role of Gimap4 in apoptosis and immunity will unfold in the future. ▪