Death-associated protein-kinase-related 2 (DRAK2) is expressed specifically by lymphocytes and is a member of the death-associated protein (DAP)-like family of serine/threonine kinases, which induce apoptosis when overexpressed by cell lines. However, as reported recently in Immunity, mice that are deficient in DRAK2 do not show defects in apoptosis; instead, T cells from these mice are hypersensitive to stimulation through the T-cell receptor (TCR).

Apoptosis has a crucial role in many aspects of immune development and immune function, including negative selection of self-reactive thymocytes and clonal contraction of the expanded T-cell pool after antigenic stimulation. So, because DRAK2 is expressed exclusively in lymphoid tissues and is a member of the DAP-like family of kinases that are known to promote apoptosis, McGargill et al. sought to investigate whether DRAK2 regulates lymphoid-cell apoptosis. DRAK2 was shown to be expressed at high levels by thymocytes (with expression increasing throughout development) and by mature T cells and B cells but not by other immune cells. Surprisingly, DRAK2-deficient mice showed no defect in negative selection. However, double positive (DP) thymocytes from these mice expressed higher levels of CD5 and CD69 than wild-type DP thymocytes, indicating that DRAK2-deficient thymocytes receive a TCR signal of greater intensity. Consistent with this observation, DRAK2-deficient T cells proliferated more and produced more cytokine in response to TCR stimulation than wild-type T cells. Furthermore, whereas crosslinking of both CD3 and CD28 is required to induce purified wild-type T cells to proliferate, purified DRAK2-deficient T cells proliferated in response to stimulation with CD3-specific antibody alone. Because the augmented proliferation of DRAK2-deficient T cells was not a result of increased cell survival after activation — that is, the defect was not in the cell-death pathways that are associated with activation — these results are consistent with a role for DRAK2 in the negative regulation of TCR-induced signals.

Analysis of the signalling pathways that are affected by DRAK2 showed that both calcium flux and phosphorylation of the signalling molecules cJUN and extracellular signal-regulated kinase 1 (ERK1) and/or ERK2 was increased following TCR stimulation of DRAK2-deficient T cells. By contrast, no difference in the phosphorylation of other signalling molecules, including TCR-ζ, LCK and p38, was observed, indicating that specific pathways downstream of the TCR are influenced by DRAK2.

Mice that are deficient in other negative regulators of T-cell activation, such as CBL-B (Casitas B-lineage lymphoma B) and CTLA4 (cytotoxic T-lymphocyte antigen 4), also have T cells that are hypersensitive to suboptimal TCR stimulation and are either equally susceptible or more susceptible to autoimmune disease than control animals. However, there were no signs of spontaneous autoimmunity in DRAK2-deficient mice. Furthermore, DRAK2-deficient animals were resistant to induced experimental autoimmune encephalomyelitis (EAE), and this correlated with a decrease in the number of cells infiltrating the central nervous system.

This study identifies a new pathway of negative regulation of T-cell activation, which is mediated by DRAK2. Understanding the surprising observation that DRAK2-deficient mice are resistant to EAE but respond normally to infection with lymphocytic choriomeningitis virus will require further study, but the authors suggest that DRAK2 could be a specific target for the treatment of autoimmune disease.