Enhanced T cell apoptosis within Drak2-deficient mice promotes resistance to autoimmunity.
Clonal expansion of T cells is vital to adaptive immunity, yet this process must be tightly controlled to prevent autoimmune disease. The serine/threonine kinase death-associated protein kinase-related apoptosis-inducing kinase 2 (DRAK2) is a negative regulator of TCR signaling and sets the threshold for the activation of naive and memory T cells and selected thymocytes. Despite enhanced T cell activation, Drak2(-/-) mice are resistant to experimental autoimmune encephalomyelitis, an autoimmune demyelinating disease that resembles multiple sclerosis. However, the basis for this autoimmune resistance is currently unknown. In this study, we show that, in the absence of DRAK2 signaling, T cells require greater tonic signaling for maintenance during clonal expansion. Following stimulation, Drak2(-/-) T cells were more sensitive to an intrinsic form of apoptosis that was prevented by CD28 ligation, homeostatic cytokines, or enforced Bcl-x(L) expression. T cell-specific Bcl-x(L) expression also restored the susceptibility of Drak2(-/-) mice to experimental autoimmune encephalomyelitis and enhanced thymic positive selection. These findings demonstrate that DRAK2 is selectively important for T cell survival and highlight the potential that DRAK2 blockade may lead to permanent autoimmune T cell destruction via intrinsic apoptosis pathways.
Ramos
Stephanie J
SJ
Department of Molecular Biology and Biochemistry, Center for Immunology, University of California, Irvine, CA 92697, USA.
Hernandez
Jeniffer B
JB
Gatzka
Martina
M
Walsh
Craig M
CM
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D051020:bcl-X Protein / Q000235:genetics / Q000276:immunology
C494812:Bcl2l1 protein, mouse; D018106:CD28 Antigens; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D051020:bcl-X Protein; C495197:Drak2 protein, mouse; D017346:Protein Serine-Threonine Kinases