Genetic Analysis of T Cells in Lupus

Yale University, New Haven CT

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Abstract

[unreadable] DESCRIPTION (provided by applicant): T cell-B cell collaboration is critical for B cell effector function and autoreactive T cell expansion in systemic lupus erythematosus (SLE). Yet consequences of such collaboration, apart from these two general outcomes, remain incompletely defined, as do the precise cellular events mediating it. Further dissection of the mechanisms that promote T-B cell collaboration and subsequent effector function is critical, as the field embarks upon therapeutic strategies in SLE that specifically target T and B cells and their interactions. We hypothesize that T-B cell collaboration in secondary lymphoid tissues in lupus leads to activation of two separable classes of CD4+ T cells, those that are necessary for B cell maturation to autoantibody-producing cells (CD4+ T B-helper cells), and those that migrate to peripheral tissues such as the kidney with the potential to incite local effector responses (CD4+ T inflammatory cells). We further hypothesize that, although distinct, development of both classes is reliant upon B cells as antigen-presenting cells (ARC) and upon interactions of ICOS (inducible costimulator) expressed on T cells with its sole ligand, B7RP-1 expressed on B cells. Our hypotheses are based in part upon our preliminary studies demonstrating that generation of class-switched autoantibodies in lupus as well as the development of inflammatory infiltrates in the kidneys is disrupted in the genetic absence of ICOS, as are the CD4+ T cell classes that possibly promote these effector outcomes; i.e., the function of both CD4+ T B-helper cells and CD4+ T inflammatory cells appears to be disrupted in ICOS-deficient lupus-prone mice. To address our hypotheses, we plan to dissect the nature of the defect(s) in B cell maturation that occurs in the absence of ICOS, characterize CD4+ T cell&that promote B cell maturation and peripheral inflammation in lupus-prone mice, and to use novel genetically-modified mice to determine the role of B7RP-1 expressed selectively on B cells, versus CD11c+ ARC, in promoting T and B cell effector function via ICOS. These are novel observations that we believe important to pursue, since pathways of activation of T helper cells with differing effector capabilities, and subsequent consequences of that activation, have been incompletely studied in lupus. Delineation of the pathways that are required for the development and maintenance of systemic autoimmunity will ultimately help foster better understanding of T-B cell collaboration as a therapeutic target in SLE. [unreadable] [unreadable] [unreadable]