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A protein called diacylglycerol kinase alpha (DGKα) could be a therapeutic target for X-linked lymphoproliferative disease (XLP-1), according to research published in Science Translational Medicine.
Researchers have known for some time that XLP-1 is a heritable disorder caused by germline mutations in SH2D1A.
When this gene is affected, it leads to defects in an adaptor molecule known as SAP (signaling lymphocytic activation molecule-associated protein), which regulates T-cell receptor signaling and triggers cytotoxic T cells to self-destruct when they are no longer needed.
Without an effective SAP adaptor molecule, apoptosis is impaired, and DGKα is activated.
With the current study, researchers wanted to determine whether the over-activation of DGKα might contribute to the reduced apoptosis observed in T cells in patients with XLP-1 and the accumulation of T cells that occurs following infection with Epstein-Barr virus.
“Patients with X-linked lymphoproliferative disease are prone to severe Epstein-Barr virus infection due to a weakened immune system,” explained study author Kim Nichols, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Infection with Epstein-Barr virus can have potentially fatal consequences for these patients. This severe disease is a double-edged sword. On the one hand, the immune system is significantly weakened. However, detrimental side effects occur due to the expansion and hyper-activation of T cells.”
“[W]e wanted to establish the biochemical mechanism underlying these changes so that we could develop better treatments for X-linked lymphoproliferative disease patients experiencing hyper-inflammation.”
Studying T cells from XLP-1 patients, the researchers found that SAP and DGKα are both crucial for the regulation of T-cell death. Loss of SAP, which normally inhibits DGKα, led to unrestrained DGKα activity, resulting in impaired T-cell receptor signaling and resistance to apoptosis.
Pharmacologic inhibition of DGKα restored the sensitivity of XLP-1 T cells to cell death. Using small interfering RNA to knockout DGKα in cultured XLP-1 T cells had the same results.
And pharmacologic inhibition of DGKα curtailed the expansion of T cells in virus-infected mice that served as a model organism to study XLP-1.
Treating the mice with a DGKα inhibitor restored T cells’ sensitivity to cell death by boosting the expression of pro-apoptotic proteins, which prevented excessive T-cell buildup and reduced the severity of the disease.
“Our findings suggest that inhibition of DGKα could reverse some of the life-threatening effects linked to Epstein-Barr virus infection of patients with X-linked lymphoproliferative disease,” Dr Nichols concluded. 
Image courtesy of NIAID
A protein called diacylglycerol kinase alpha (DGKα) could be a therapeutic target for X-linked lymphoproliferative disease (XLP-1), according to research published in Science Translational Medicine.
Researchers have known for some time that XLP-1 is a heritable disorder caused by germline mutations in SH2D1A.
When this gene is affected, it leads to defects in an adaptor molecule known as SAP (signaling lymphocytic activation molecule-associated protein), which regulates T-cell receptor signaling and triggers cytotoxic T cells to self-destruct when they are no longer needed.
Without an effective SAP adaptor molecule, apoptosis is impaired, and DGKα is activated.
With the current study, researchers wanted to determine whether the over-activation of DGKα might contribute to the reduced apoptosis observed in T cells in patients with XLP-1 and the accumulation of T cells that occurs following infection with Epstein-Barr virus.
“Patients with X-linked lymphoproliferative disease are prone to severe Epstein-Barr virus infection due to a weakened immune system,” explained study author Kim Nichols, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Infection with Epstein-Barr virus can have potentially fatal consequences for these patients. This severe disease is a double-edged sword. On the one hand, the immune system is significantly weakened. However, detrimental side effects occur due to the expansion and hyper-activation of T cells.”
“[W]e wanted to establish the biochemical mechanism underlying these changes so that we could develop better treatments for X-linked lymphoproliferative disease patients experiencing hyper-inflammation.”
Studying T cells from XLP-1 patients, the researchers found that SAP and DGKα are both crucial for the regulation of T-cell death. Loss of SAP, which normally inhibits DGKα, led to unrestrained DGKα activity, resulting in impaired T-cell receptor signaling and resistance to apoptosis.
Pharmacologic inhibition of DGKα restored the sensitivity of XLP-1 T cells to cell death. Using small interfering RNA to knockout DGKα in cultured XLP-1 T cells had the same results.
And pharmacologic inhibition of DGKα curtailed the expansion of T cells in virus-infected mice that served as a model organism to study XLP-1.
Treating the mice with a DGKα inhibitor restored T cells’ sensitivity to cell death by boosting the expression of pro-apoptotic proteins, which prevented excessive T-cell buildup and reduced the severity of the disease.
“Our findings suggest that inhibition of DGKα could reverse some of the life-threatening effects linked to Epstein-Barr virus infection of patients with X-linked lymphoproliferative disease,” Dr Nichols concluded.
Image courtesy of NIAID
A protein called diacylglycerol kinase alpha (DGKα) could be a therapeutic target for X-linked lymphoproliferative disease (XLP-1), according to research published in Science Translational Medicine.
Researchers have known for some time that XLP-1 is a heritable disorder caused by germline mutations in SH2D1A.
When this gene is affected, it leads to defects in an adaptor molecule known as SAP (signaling lymphocytic activation molecule-associated protein), which regulates T-cell receptor signaling and triggers cytotoxic T cells to self-destruct when they are no longer needed.
Without an effective SAP adaptor molecule, apoptosis is impaired, and DGKα is activated.
With the current study, researchers wanted to determine whether the over-activation of DGKα might contribute to the reduced apoptosis observed in T cells in patients with XLP-1 and the accumulation of T cells that occurs following infection with Epstein-Barr virus.
“Patients with X-linked lymphoproliferative disease are prone to severe Epstein-Barr virus infection due to a weakened immune system,” explained study author Kim Nichols, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Infection with Epstein-Barr virus can have potentially fatal consequences for these patients. This severe disease is a double-edged sword. On the one hand, the immune system is significantly weakened. However, detrimental side effects occur due to the expansion and hyper-activation of T cells.”
“[W]e wanted to establish the biochemical mechanism underlying these changes so that we could develop better treatments for X-linked lymphoproliferative disease patients experiencing hyper-inflammation.”
Studying T cells from XLP-1 patients, the researchers found that SAP and DGKα are both crucial for the regulation of T-cell death. Loss of SAP, which normally inhibits DGKα, led to unrestrained DGKα activity, resulting in impaired T-cell receptor signaling and resistance to apoptosis.
Pharmacologic inhibition of DGKα restored the sensitivity of XLP-1 T cells to cell death. Using small interfering RNA to knockout DGKα in cultured XLP-1 T cells had the same results.
And pharmacologic inhibition of DGKα curtailed the expansion of T cells in virus-infected mice that served as a model organism to study XLP-1.
Treating the mice with a DGKα inhibitor restored T cells’ sensitivity to cell death by boosting the expression of pro-apoptotic proteins, which prevented excessive T-cell buildup and reduced the severity of the disease.
“Our findings suggest that inhibition of DGKα could reverse some of the life-threatening effects linked to Epstein-Barr virus infection of patients with X-linked lymphoproliferative disease,” Dr Nichols concluded.