Clast1/LR8: A Novel Target for the Modulation of Microglial Function and CNS Autoimmunity

Monica Carson, Ph.D.

University of California, Riverside

Funded in September, 2006: $200000 for 3 years


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Does a Specific Molecule Govern Immune Tolerance and Intolerance?

Researchers will determine whether a specific molecule governs immune T cells’ “intolerance” to the body’s own tissues (as occurs in autoimmune diseases) and, conversely, “tolerance” to brain tumors that invade and take over brain cells.   

Ironically, activation of immune T cells in autoimmune diseases results in destruction of the body’s own tissues, while therapies aimed at promoting attacks by T cells against aggressive brain tumors fail. T cells fail to attack brain tumors, in part because the tumors create an environment that suppresses initiation of these immune responses. Ordinarily, T cell responses are initiated through the cells’ interactions with “antigen-presenting cells” (APCs).  These include immune macrophages and microglial and dendritic cells.  APCs ordinarily capture, process, and present a specific invader to immune T cells. When this process goes awry in autoimmune diseases, somehow the body’s own tissues are misidentified as invaders.  Conversely, the process fails to initiate an immune attack against brain tumors. The investigators, therefore, are studying how APCs either activate or turn-off immune T cells.

Whether or not APCs effectively initiate immune T cell attacks may depend on a molecule called “LR8.”  The researchers hypothesize that this molecule is absent when T cells attack the body’s own tissues in autoimmune diseases, but present when T cells appropriately attack invaders. By studying T cell-APC interactions in tissue cultures in the lab and in a mouse model of autoimmune MS, the investigators will see whether manipulating the levels of LR8 alters the abilities of APCs to capture, process, and present a defined agent to immune T cells.  The answer should help determine whether LR8 causes T cells’ destructive or protective actions, or is simply associated with those actions. 

Significance:  If this molecule is found to directly regulate T cells-APC interactions, the research may eventually lead to development of therapies that prevent T cell attacks in autoimmune diseases and transplantation and therapies that strengthen T cell attacks on brain tumors.


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Clast1/LR8: A Novel Target for the Modulation of Microglial Function and CNS Autoimmunity

Inflammation and T cell responses promote both wound healing and provide pathogen defense. However, many CNS disorders result from inappropriate direction of autoimmune responses against essential CNS elements (for example, multiple sclerosis).  In addition, the ability to treat many chronic CNS degenerative disorders (for example, Parkinson’s disease) with transplant therapies of healthy cells or even stem cells is limited by their propensity of partially matched transplant tissue to elicit destructive T cell responses, ultimately leading to transplant rejection.  Our lab uses bone marrow chimeric methodologies coupled with gene expression profiling to define the molecular features associated with destructive versus protective/benign autoimmunity.  Our goal is to define events that regulate the “tipping point” between destructive and protective/benign autoimmunity. In our ongoing studies, we have identified a novel target for the modulation of microglial function and CNS autoimmunity: clast1/LR8.  LR8 is a tetraspan CD20-related molecule.  We find that its expression is absent during the initiation of destructive auto-reactive T cell responses (for example, during EAE), but present during induction of protective T cell responses (for example, following facial axotomy).

We therefore, hypothesize that Clast1/LR8 expression is causative in inducing a neuroprotective and/or partly tolerogenic antigen-presenting cell (APC) phenotype. Here we propose to generate lentiviral reagents to modulate LR8 expression (up and down) in the antigen-presenting cells that are likely to contribute to the promotion of destructive anti-CNS T cell responses. We will utilize in vitro and in vivo assays to test whether and to what extent LR8 expression is causative in regulating the APC function of microglia, macrophages and dendritic cells.  We will also examine whether modulating of LR8 expression can alter the incidence, severity, or kinetics of experimentally induced autoimmune encephalomyelitis (EAE).