Development and Function of Natural Autoreactive B Cells

Institute For Cancer Research, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): Although it is widely accepted that B cells with self-reactivity are deleted or rendered functionally inactive, self-reactive antibodies, referred to as "natural autoantibodies," can be found in the serum of healthy animals, in an apparent paradox to the clonal tolerance theory. An anti-thymocyte/T cell autoantibody (ATA) encoded by VH3609/Vk21C germline genes is such a natural antibody, derived from CD5+ B cells (B-1) in mice, the population predominantly responsible for natural autoantibody secretion. ATA recognizes a developmentally regulated T cell specific carbohydrate epitope on the Thy-1/CD9O glycoprotein expressed on thymocytes, helper T cells and tumors. Our previous work with VH3609mu transgenic mice (ATAmuTg) demonstrated that the generation of ATA B cells and the secretion of serum ATA required self-antigen, since both were absent from Thy-I knockout mice. Here we propose to investigate why this positive selection occurs. By establishing and characterizing VH3609mu/Vkappa29C double transgenic mice (ATAmu kappaTg), we will identify the developmental stage(s) of B cell positive selection (Aim 1). To investigate if the antigen form is critical for positive selection, we will establish Thy-1 transgenic mouse lines expressing either transmembrane or secreted Thy-1 (Aim 2). In Aim 3 we will test whether positive selection is a unique feature of "B-1" B cell development, selecting in favor of natural autoreactive specificities. The possibility of differences in selection threshold between "B-1" versus "B-2" B cell development will be tested by stem cell reconstitution experiments using precursors expressing BCRs of varying affinity to Thy-I after retroviral transduction (Aim 3). Accomplishing these aims will help to establish a more complete picture of antigen receptor repertoire selection in B cell development and will test our hypothesis that natural autoreactive B cell generation is a part of the innate immune system, restricted to "B-1" development. "B-1" may actively produce certain autoreactive B cells essential for immune protection, preserving important lymphocyte clones for the rest of life to serve in immunologic surveillance.