Anti-viral effector T cell responses and trafficking are not dependent upon DRAK2 signaling following viral infection of the central nervous system

Abstract

The signaling events involved in T cell trafficking into the central nervous system (CNS) following viral infection are not fully understood. Intracerebral infection of mice with mouse hepatitis virus (MHV) results in an acute encephalomyelitis followed by an immune-mediated demyelinating disease. Although chemokine signaling is critical in promoting T cell infiltration into the CNS and control of viral replication, additional signaling pathways have not been completely explored. DRAK2, a lymphoid-restricted serine/threonine kinase, prevents spurious T cell activation. Yet Drak2- / - mice are resistant to MOG-induced experimental autoimmune encephalomyelitis (EAE), suggesting that DRAK2 may influence T cell trafficking into the CNS. In order to further characterize the molecular mechanisms governing T cell activation and accumulation within the CNS in response to viral infection, MHV was instilled into the CNS of Drak2- / - mice. Drak2-deficient T cells possessed no obvious defects in trafficking into the CNS following MHV infection. Moreover, Drak2-deficient T cell activation, expansion and cytokine production were unimpaired in response to acute MHV infection. These results demonstrate that DRAK2 signaling is dispensable for T cell recruitment into the CNS following viral infection, suggesting that the resistance of Drak2- / - mice to EAE is not due to overt T cell trafficking defects.

Drak2 Regulates the Survival of Activated T Cells and Is Required for Organ-Specific Autoimmune Disease

“…The number of mice that displayed signs of disease and the severity of symptoms were dramatically reduced in Drak2 –/– mice. This did not reflect a generalized lack of immune competence, because Drak2 –/– mice mounted normal immune responses to acute infection by foreign pathogens, including the following: lymphocytic choriomeningitis virus (LCMV), Listeria monocytogenes (data not shown), and mouse hepatitis virus (MHV) (22). This observation raises the intriguing question of how an increased sensitivity in T cells results in decreased autoimmune disease.…”

The Role of Drak2 in T Cell Function and Autoimmunity

“…Therefore, the reduction in viral load was attributed to reduced T cell infiltration in the CNS in response to WNV infection. Lastly, Drak2 -/-mice respond similar to wildtype mice during intra-cerebral and intraperitoneal infection with mouse hepatitis virus in terms of T cell activation, expansion, and cytokine production [25,26]. Surprisingly, memory T cell function was enhanced in the absence of Drak2.…”

“…Yet, Drak2 -/-mice respond comparably to wildtype mice in several models of infection. In fact, the response is enhanced in the absence of Drak2 following infection with some pathogens [24][25][26] and (unpublished data). Furthermore, Drak2 does not function as a tumor suppressor or an oncogene in various in vivo tumor models [32].…”

“…NOD mice spontaneously develop diabetes, and disease etiology is similar to T1D in humans, including the involvement of autoreactive T cells, autoantibodies, and similar genetic risk factors [43]. Interestingly, despite the diminished autoimmunity, Drak2 -/-mice effectively eliminate infectious pathogens and retain the ability to combat tumors similar to wildtype mice [23][24][25][26]32]. Thus, Drak2 is an ideal protein to target in order to treat autoimmune disorders without compromising immunity to pathogens and tumors.…”

“…Studies showed that wildtype and Drak2 -/-T cells exhibited similar expression levels of the adhesion molecules and chemokine receptors required for entry into the CNS [23], however it was not clear whether these receptors functioned similarly in the absence of Drak2. Furthermore, although the migration of T cells into nonlymphoid organs during delayed-type hypersensitivity, LCMV infection, and mouse hepatitis virus (MHV) was not altered in the absence of Drak2 [23,25], the mechanisms that mediate migration of T cells into non-lymphoid organs may vary between infection and autoimmunity. We showed that T cell migration in response to CCL19, a chemoattractant that is also expressed in the CNS, was decreased in the absence of Drak2.…”