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Utilization of a Photoactivatable Antigen System to Examine B-Cell Probing Termination and the B-Cell Receptor Sorting Mechanisms During B-Cell Activation

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Utilization of a photoactivatable antigen system to examine B-cell probing termination and the B-cell receptor sorting mechanisms during B-cell activation Jing Wanga,1, Shan Tangb,1, Zhengpeng Wana, Yiren Gaoa, Yiyun Caoa, Junyang Yia, Yanyan Sib, Haowen Zhanga, Lei Liub,2, and Wanli Liua,2 aKey Laboratory of Protein Sciences (Ministry of Education), Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Institute of Immunology, Tsinghua University, Beijing 100084, China; and bTsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China Edited by Ulrich von Andrian, Harvard Medical School, Boston, MA, and accepted by the Editorial Board December 10, 2015 (received for review September 4, 2015) Antigen binding to the B-cell receptor (BCR) induces several re- initiation of B-cell activation process the information of antigen sponses, resulting in B-cell activation, proliferation, and differentia- specificity, density, affinity, valency, mobility, substrate stiffness, tion. However, it has been difficult to study these responses due to and mechanical forces in such an efficient way? To attempt to their dynamic, fast, and transient nature. Here, we attempted to solve address this intriguing question, a detailed understanding of the this problem by developing a controllable trigger point for BCR and precise BCR sorting mechanisms within the B-cell IS during the antigen recognition through the construction of a photoactivatable initiation of B-cell activation is required. However, it is technically antigen, caged 4-hydroxy-3-nitrophenyl acetyl (caged-NP). This pho- difficult to accurately capture these events due to their fast and toactivatable antigen system in combination with live cell and single dynamic nature. It is challenging to capture an entire molecular molecule imaging techniques enabled us to illuminate the previously event from the same B-cell before and immediately after antigen unidentified B-cell probing termination behaviors and the precise BCR recognition, and it is more difficult to capture multiple events in sorting mechanisms during B-cell activation. B cells in contact with parallel from multiple cells in a synchronized manner. An attractive caged-NP exhibited probing behaviors as defined by the unceasing solution for this dilemma is to develop a precisely controllable trigger extension of membrane pseudopods in random directions. Further point for BCR and antigen recognition by using photoactivatable analyses showed that such probing behaviors are cell intrinsic antigens, which are initially inactive but become immediately active with strict dependence on F-actin remodeling but not on tonic on the illumination of UV light. Indeed, photoactivatable systems BCR signaling. B-cell probing behaviors were terminated within 4 s have been used to investigate the kinetics of second-messenger after photoactivation, suggesting that this response was sensitive activity through caged calcium (22) and caged cAMP (23). Ad- and specific to BCR engagement. The termination of B-cell probing ditionally, the T-cell receptor was studied using major histo- was concomitant with the accumulation response of the BCRs into compatibility complex (MHC) presenting photoactivatable peptide the BCR microclusters. We also determined the Brownian diffusion (24, 25). coefficient of BCRs from the same B cells before and after BCR In this report, we dissected the dynamic responses during the engagement. The analysis of temporally segregated single molecule initiation of B-cell activation by using a photoactivatable antigen images of both BCR and major histocompatibility complex class I based experimental system in combination with high-resolution high (MHC-I) demonstrated that antigen binding induced trapping of BCRs into the BCR microclusters is a fundamental mechanism for B cells to Significance acquire antigens. B-cell receptor (BCR) and antigen engagement induces several B-cell receptor | photoactivatable antigen | caged-NP | B-cell activation | responses resulting in B-cell activation. However, it has been single molecule imaging difficult to study these responses due to their dynamic nature. To solve this problem, a photoactivatable antigen, caged he immune system uses immune receptors to sense and ac- 4-hydroxy-3-nitrophenyl acetyl (caged-NP), was developed. B cells Tquire antigens. Antigen binding induces a series of dynamic contacting caged-NP exhibited probing behaviors that are cell changes in the biophysical behaviors and biochemical features of intrinsic with strict dependence on F-actin remodeling. B-cell the immune receptors, and these changes determine the fate of a probing behaviors were terminated within 4 s after the pho- cell (1–3). However, it has been difficult to accurately capture toactivation of caged-NP. The termination of B-cell probing was and thus comprehensively investigate these changes because they concomitant with the accumulation response of the BCRs into usually occur very quickly after immune recognition (1, 4). For the BCR microclusters. The analysis of temporally segregated example, recent live cell imaging studies showed that the B lym- single molecule images demonstrated that antigen binding in- phocytes swiftly accumulate the surface-expressed B-cell receptors duced trapping of BCRs into the BCR microclusters is a funda- (BCRs) into the contact interface between the B cells and the mental mechanism for B cells to acquire antigens. antigen-presenting substrates to form a specialized membrane structure, the B-cell immunological synapse (IS) (1, 4). More- Author contributions: L.L. and W.L. designed research; J.W., S.T., Z.W., and Y.G. per- formed research; J.W., S.T., J.Y., Y.S., and H.Z. contributed new reagents/analytic tools; over, both our studies and those of others showed that these J.W., Y.C., J.Y., and H.Z. analyzed data; and W.L. wrote the paper. accumulation events are sensitive to the biochemical and bio- The authors declare no conflict of interest. physical features of the antigens that B cells likely encounter in This article is a PNAS Direct Submission. U.v.A. is a guest editor invited by the Editorial vivo (4, 5). These features include but are not limited to antigen Board. – density (6, 7), antigen affinity (6, 7), antigen valency (8 13), the 1J.W. and S.T. contributed equally to this work. – mobility of the antigen (14 17), the stiffness of the substrates 2To whom correspondence may be addressed. Email: [email protected] or liuwanli@ presenting the antigen (18, 19) and the mechanical forces de- biomed.tsinghua.edu.cn. livered to the BCRs by the antigens (20, 21). These facts high- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. light a long-standing question in immunology: how can the 1073/pnas.1517612113/-/DCSupplemental. E558–E567 | PNAS | Published online January 13, 2016 www.pnas.org/cgi/doi/10.1073/pnas.1517612113 Downloaded by guest on October 6, 2021 speed total internal reflection fluorescence microscopy (TIRFM) AB PNAS PLUS imaging techniques. We caged the widely used model antigen caged-NP WT-NP 4-hydroxy-3-nitrophenyl acetyl (caged-NP) that is only con- verted to its antigenic form after exposure to UV photons. The O2N O caged-NP O2N photoactivation of caged-NP in contact with NP-specific B1-8- O – O O BCR expressing B cells provides a precisely controllable trigger a) point to perform high resolution temporal analyses of the for- HN caging group mation of BCR microclusters and the B-cell IS in response to an- NP O 5 b) tigen stimulation. By combining the unique strengths of the caged- – Ala-Ser-Thr-Gly-Lys-Thr-Ala-Ser-Ala-Cys- 15 20 25 30 NP based photoactivatable antigen system with TIRFM-based live Thr-Ser-Gly-Ala-Ser-Ser-Thr-Gly-Ser-His Retention time (min) cell and single molecule imaging techniques, we examined the basal 6 response of a quiescent B cell exposed to coverslips presenting the C D caged-NP for 360 s and then examined the changes in the responses a) 916.1 of the same B cell immediately after the recognition of the pho- 1373.7 100 687.3 toactivated-NP antigen for another360s.Toourknowledge,this 80 system represents the first temporally seamless imaging ex- 600 1100 1600 m/z 60 perimental procedure for the study of the molecular events during caged-NP peptide 981.2 40 photolyzed-NP peptide the initiation of B-cell activation. We illuminated the probing be- b) haviors in quiescent B cells as defined by the unceasing extension 20 1471.1 % total of peptide of membrane pseudopods in random directions. We found that 736.1 0 BCR and antigen recognition promptly terminated the probing 0 20 40 60 responses. We also dissected the sophisticated BCR sorting mech- 600 1100 1600 m/z Time (s) anism within the B-cell IS during the initiation of B-cell activation. E 1.5 WT-NP-0 s Results WT-NP-30 s 1.0 WT-NP-120 s The Development of a Caged-NP–Based Photoactivatable Antigen WT-NP-300 s System. The NP hapten is specifically recognized by B1-8 antibody or caged-NP-0 s – 0.5 caged-NP-30 s B1-8-BCR expressing B cells mainly due to the hydroxyl (-OH) OD 490 nm group in the phenol ring (26). To mask the antigenicity of NP, we caged-NP-120 s 0.0 caged-NP-300 s conjugated a UV-sensitive moiety, 4,5-dimethoxy-2-nitrobenzyl 0 5 10 15 20 (DMNB) to its -OH group to generate DMNB-NP (Fig. 1A Antigen concentration (μg/mL) 1 13 and Fig. S1). Analyses by H- and C-NMR verified the correct con- – jugation of DMNB to NP (Fig. S2 A and B). To facilitate the Fig. 1. The development of a caged-NP based photoactivatable antigen system.
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