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Proapoptotic Protein Bim Is Differentially Required During Thymic Clonal Deletion to Ubiquitous Versus Tissue-Restricted Antigens

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Proapoptotic Protein Bim Is Differentially Required During Thymic Clonal Deletion to Ubiquitous Versus Tissue-Restricted Antigens Proapoptotic protein Bim is differentially required during thymic clonal deletion to ubiquitous versus tissue-restricted antigens Alexander Y. W. Suen and Troy A. Baldwin1 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada T6G 2S2 Edited by Michael J. Bevan, University of Washington, Seattle, WA, and approved December 8, 2011 (received for review September 8, 2011) Positive and negative selection of thymocytes in the thymus are positively selected by high-affinity antigen encounter in the thy- critical for the development of a mature and self-tolerant T-cell mus (6). One such example are T-regulatory (Treg) cells, which repertoire. The proapoptotic Bcl-2 family member Bim is important are believed to require high-affinity interactions to develop in the for negative selection by inducing apoptosis in thymocytes receiv- medulla (7). It remains unknown what drives this distinction ing a strong signal through their antigen receptor. However, in the between negative selection and Treg development, although case of ubiquitous self-antigens (UbA), Bim is not required for the secondary signals, such as TGF-β, may play a role in overcoming clonal deletion of self-reactive thymocytes, suggesting the exis- cell death (8). tence of nonapoptotic clonal deletion mechanisms. Unlike UbA, Although it is unclear how the same TCR can transduce a sig- clonal deletion to tissue-restricted antigens (TRAs) requires posi- nal for positive or negative selection, differential mitogen-acti- tive selection and CCR7-mediated migration to the medulla. This vated protein kinase signaling appears to play a role, ultimately led us to hypothesize that Bim is required for the latter. To study leading to the activation of different transcriptional programs (9). the role of Bim in clonal deletion to TRA, we constructed bone Negative selection induces expression of proapoptotic molecules marrow (BM) chimeras using OT-I Bim-deficient or -sufficient do- such as the Bcl-2 homology domain 3 (BH3) only Bcl-2 family nor bone marrow and recipients that express membrane bound member Bim (10, 11), which is essential for the intrinsic pathway chicken ovalbumin under control of the rat insulin promoter (Rip- of apoptosis (12). It was generally held that Bim-mediated apo- IMMUNOLOGY mOVA). We found that clonal deletion to TRA was completely ptosis was required for negative selection (13). This was supported abrogated in the absence of Bim and large numbers of mature by the fact that Bim-deficient mice develop late onset autoim- OT-I CD8 T cells survived in the periphery. Despite the large num- mune disease and that nonobese diabetic mice, which spontane- bers of autoreactive T cells, the chimeras did not develop diabetes ously develop diabetes, have a defect in the induction of Bim (11, and OT-I Bim-deficient T cells from these chimeras were function- 14, 15). In contrast to this paradigm, recent studies demonstrated ally impaired. Collectively, these data provide unique evidence of that, whereas Bim is required for thymocyte apoptosis, it is not a differential, thymocyte-intrinsic, molecular requirement down- required for clonal deletion to the ubiquitous s-mcy male peptide stream of the T-cell receptor (TCR) for clonal deletion to UbA ver- (16, 17) or superantigen-mediated clonal deletion (18). sus TRA and highlight the profound ability of other tolerance It is clear that negative selection is induced by two different mechanisms to control T-cell autoreactivity in the absence of thy- classes of self-antigens: ubiquitous self-antigens (UbA) and tis- mic clonal deletion. sue-restricted antigens (TRAs). TRA expression is restricted to the medulla with expression of many TRAs controlled by the autoimmunity | thymocyte development AIRE gene (19). After much debate, recent data suggest that negative selection of DP thymocytes to UbA occurs in the cortex uring T-cell development, the T-cell receptor (TCR) is without medullary involvement (20), whereas positive selection Dgenerated by random rearrangements at the TCRα and and CCR7-dependent migration to the medulla are required for TCRβ loci. This allows for a large variety of TCR specificities to negative selection to TRA (4). Once in the medulla, CD4+CD8lo be generated but also requires that T cells be educated. The or CD4loCD8lo thymocytes can interact with mTECs that directly education process ensures that the T cells can respond to antigen present TRA or DCs that can cross-present TRAs derived from in the context of self-major histocompatibility complex (MHC) mTECs (5). Therefore, negative selection to UbA and TRA molecules but cannot respond to self-antigens in the context of differ with respect to the developmental stage of the thymocyte self-MHC. These selection events begin at the CD4+CD8+ and the anatomical location within the thymus. These factors double-positive (DP) stage of thymocyte development within the may result in differential molecular requirements for negative cortex of the thymus. DP thymocytes may undergo one of three selection to UbA versus TRA, although no such thymocyte in- fates depending on the affinity of their TCR for self-peptide trinsic differences downstream of the TCR have been reported. presented on self-MHC (pMHC) on cortical thymic epithelial Using OT-I TCR transgenic bone marrow (BM) and mice cells (1). If the TCR cannot functionally interact with self- expressing membrane bound chicken ovalbumin (mOVA) under pMHC, the thymocytes die by neglect. Thymocytes expressing control of the chicken β-actin promoter (Act-mOVA) (21) or rat a TCR with high affinity for self-pMHC undergo negative se- insulin promoter (RIP-mOVA) (22), we demonstrate that unlike lection, resulting in the elimination of that particular TCR clonal deletion to UbA, Bim is required for clonal deletion to − − specificity from the T-cell repertoire. Low or moderate affinity TRA. Although OT-I Bim / CD8 T cells are abundant in RIP- interactions between the TCR and self-pMHC result in positive selection, leading to thymocyte survival and subsequent differ- + + entiation into CD4 or CD8 single-positive (SP) thymocytes Author contributions: A.Y.W.S. and T.A.B. designed research; A.Y.W.S. performed (1). These positively selected thymocytes then undergo CCR7- research; A.Y.W.S. and T.A.B. analyzed data; and A.Y.W.S. and T.A.B. wrote the paper. dependent migration to the thymic medulla (2). During the 3- to The authors declare no conflict of interest. 4-d residence in the medulla (3), SP thymocytes are subjected to This article is a PNAS Direct Submission. a further round of negative selection through interactions with 1To whom correspondence should be addressed. E-mail: [email protected]. medullary thymic epithelial cells (mTECs) and medullary den- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. dritic cells (DCs) (4, 5). Interestingly, some T-cell subsets are 1073/pnas.1114834109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1114834109 PNAS Early Edition | 1of6 Downloaded by guest on September 26, 2021 mOVA chimeras, they do not cause diabetes, but rather are Bim Is Required for Clonal Deletion to TRA. Despite the lack of re- impaired in their response to antigen. quirement for Bim in clonal deletion in the OT-I model and other models, the fact remains that Bim deficiency leads to au- Results toimmune disorders (14). Whereas the previous models exam- Bim Is Not Required for Clonal Deletion to UbA. Recently, it has ined clonal deletion to UbA or superantigen they did not address become clear that Bim is not required for clonal deletion in clonal deletion to TRA, which differs with respect to the de- a number of physiological model systems (16, 17). However, in velopmental stage of the thymocyte and anatomical location these models, the high-affinity antigen was expressed ubiqui- within the thymus. We hypothesized that these distinctions may tously and therefore the role of Bim in clonal deletion to TRA is result in a difference in the requirement for Bim in clonal de- still unclear. As these models are not easily manipulated to ex- letion to TRA. amine clonal deletion to TRA, we sought to use the OT-I TCR To generate a model of clonal deletion to TRA, we grafted −/− transgenic system. OT-I thymocytes express a TCR specific for OT-I or OT-I Bim BM to RIP-mOVA recipients. The rat the SIINFEKL peptide of OVA in the context of H-2Kb and can insulin promoter drives expression of mOVA in the pancreas, the be detected using an anti-Vα2 mAb. Furthermore, mice that kidney, and the medulla of the thymus. In this model, OT-I fi express membrane OVA ubiquitously or in a tissue-restricted thymocytes will rst undergo positive selection in the cortex fashion are available. To ensure that clonal deletion of OT-I before encountering their cognate antigen in the medulla. The fi α + → thymocytes to UbA was Bim independent, we generated BM CD4/CD8 thymic pro les of V 2 thymocytes from OT-I B6 −/−→ chimeras using Act-mOVA recipients and either OT-I or OT-I and OT-I Bim B6 chimeras were not drastically altered by − − fi A Bim / BM donors. We found that Bim deficiency did not affect Bim de ciency (Fig. 2 ). In contrast and as previously demon- fi α + strated (23), the OT-I→RIP-mOVA chimeras displayed a signif- the CD4/CD8 thymic pro les of V 2 thymocytes in the OT-I + −/− icant reduction in the proportion of Vα2 CD8SP thymocytes Bim →B6 chimeras compared with the OT-I→B6 chimeras + int with an increase in the DN compartment (Fig. 2A). Contrary to (Fig. 1A). In both cases, DP, CD4 CD8 , and CD8SP thymo- − − the OT-I→RIP-mOVA chimeras, the OT-I Bim / →RIP-mOVA cyte percentages were similar (Fig.
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