Proapoptotic protein Bim is differentially required during thymic clonal deletion to ubiquitous versus tissue-restricted antigens

Abstract

Positive and negative selection of thymocytes in the thymus are critical for the development of a mature and self-tolerant T-cell repertoire. The proapoptotic Bcl-2 family member Bim is important for negative selection by inducing apoptosis in thymocytes receiving a strong signal through their antigen receptor. However, in the case of ubiquitous self-antigens (UbA), Bim is not required for the clonal deletion of self-reactive thymocytes, suggesting the existence of nonapoptotic clonal deletion mechanisms. Unlike UbA, clonal deletion to tissue-restricted antigens (TRAs) requires positive selection and CCR7-mediated migration to the medulla. This led us to hypothesize that Bim is required for the latter. To study the role of Bim in clonal deletion to TRA, we constructed bone marrow (BM) chimeras using OT-I Bim-deficient or -sufficient donor bone marrow and recipients that express membrane bound chicken ovalbumin under control of the rat insulin promoter (RipmOVA). We found that clonal deletion to TRA was completely abrogated in the absence of Bim and large numbers of mature OT-I CD8 T cells survived in the periphery. Despite the large numbers of autoreactive T cells, the chimeras did not develop diabetes and OT-I Bim-deficient T cells from these chimeras were functionally impaired. Collectively, these data provide unique evidence of a differential, thymocyte-intrinsic, molecular requirement downstream of the T-cell receptor (TCR) for clonal deletion to UbA versus TRA and highlight the profound ability of other tolerance mechanisms to control T-cell autoreactivity in the absence of thymic clonal deletion.autoimmunity | thymocyte development

Differential Roles for Bim and Nur77 in Thymocyte Clonal Deletion Induced by Ubiquitous Self-Antigen

“…Through interactions with pro-and antiapoptotic Bcl-2 family members at mitochondria, Bim promotes release of cytochrome c and subsequent caspase activation. Unlike the critical role of Bim in TRA-mediated clonal deletion (15,16), Bim is not required for deletion in the HY cd4 model or other UbA-driven models (12,15,17). However, we found that Bim was essential for caspase-3 activation in thymocytes, suggesting that clonal deletion in HY cd4 Bim 2/2 mice was mediated by a caspase-independent cell death mechanism.…”

“…In support of this, phosphorylation and subcellular localization of Nur77 have been shown to be different between stimulated DP thymocytes and mature CD8 + T cells (48). Likewise, in contrast to its lesser impact on UbA-mediated clonal deletion, Bim deficiency is known to block TRA-mediated deletion of CD8SP thymocytes (15,16). Given these context-dependent differences in the mechanism of clonal deletion, it would be of interest to assess the role of Nur77 in TRA-mediated deletion of CD8SP thymocytes as well.…”

Loss of Timp3 Gene Leads to Abdominal Aortic Aneurysm Formation in Response to Angiotensin II

“…Bone Marrow Reconstitution-Bone marrow (BM) reconstitution was performed to generate chimeric mice as described previously (26). Donor WT and Timp3…”

Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells

“…Although the thymic cortex is necessary for thymocyte expansion and positive selection, the primary role of the thymic medulla is in the generation of selftolerance via negative selection and the generation of regulatory T cells (3)(4)(5). Failure to establish or maintain self-tolerance causes autoimmunity, which has a major impact on human health.…”