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1. Thymic regulatory T cells arise via two distinct developmental programs

Author

Owen, David L, Mahmud, Shawn A, Sjaastad, Louisa E, Williams, Jason B, Spanier, Justin A, Simeonov, Dimitre R, Ruscher, Roland, Huang, Weishan, Proekt, Irina, Miller, Corey N, Hekim, Can, Jeschke, Jonathan C, Aggarwal, Praful, Broeckel, Ulrich, LaRue, Rebecca S, Henzler, Christine M, Alegre, Maria-Luisa, Anderson, Mark S, August, Avery, Marson, Alexander, Zheng, Ye, Williams, Calvin B, and Farrar, Michael A

Subjects
Biomedical and Clinical Sciences, Immunology, HIV/AIDS, Stem Cell Research, Prevention, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Animals, Autoantigens, Cell Differentiation, Colitis, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Forkhead Transcription Factors, Freund's Adjuvant, Humans, Immune Tolerance, Interleukin-2 Receptor alpha Subunit, Lymphoid Progenitor Cells, Mice, Mice, Transgenic, Mycobacterium tuberculosis, Myelin-Oligodendrocyte Glycoprotein, Peptide Fragments, Signal Transduction, Specific Pathogen-Free Organisms, T-Lymphocytes, Regulatory, Thymus Gland, Biochemistry and cell biology
Abstract

The developmental programs that generate a broad repertoire of regulatory T cells (Treg cells) able to respond to both self antigens and non-self antigens remain unclear. Here we found that mature Treg cells were generated through two distinct developmental programs involving CD25+ Treg cell progenitors (CD25+ TregP cells) and Foxp3lo Treg cell progenitors (Foxp3lo TregP cells). CD25+ TregP cells showed higher rates of apoptosis and interacted with thymic self antigens with higher affinity than did Foxp3lo TregP cells, and had a T cell antigen receptor repertoire and transcriptome distinct from that of Foxp3lo TregP cells. The development of both CD25+ TregP cells and Foxp3lo TregP cells was controlled by distinct signaling pathways and enhancers. Transcriptomics and histocytometric data suggested that CD25+ TregP cells and Foxp3lo TregP cells arose by coopting negative-selection programs and positive-selection programs, respectively. Treg cells derived from CD25+ TregP cells, but not those derived from Foxp3lo TregP cells, prevented experimental autoimmune encephalitis. Our findings indicate that Treg cells arise through two distinct developmental programs that are both required for a comprehensive Treg cell repertoire capable of establishing immunotolerance.

Published
2019

3. Patients with juvenile idiopathic arthritis have decreased clonal diversity in the CD8+ T cell repertoire response to influenza vaccination.

Author

Sabbagh, Sara E., Haribhai, Dipica, Gershan, Jill A., Verbsky, James, Nocton, James, Yassai, Maryam, Naumova, Elena N., Hammelev, Erin, Dasgupta, Mahua, Ke Yan, Gorski, Jack, and Williams, Calvin B.

Subjects
JUVENILE idiopathic arthritis, T cells, INFLUENZA vaccines, IMMUNOSUPPRESSIVE agents
Abstract

Recurrent exposures to a pathogenic antigen remodel the CD8+ T cell compartment and generate a functional memory repertoire that is polyclonal and complex. At the clonotype level, the response to the conserved influenza antigen, M158-66 has been well characterized in healthy individuals, but not in patients receiving immunosuppressive therapy or with aberrant immunity, such as those with juvenile idiopathic arthritis (JIA). Here we show that patients with JIA have a reduced number of M158-66 specific RS/RA clonotypes, indicating decreased clonal richness and, as a result, have lower repertoire diversity. By using a rank-frequency approach to analyze the distribution of the repertoire, we found several characteristics of the JIA T cell repertoire to be akin to repertoires seen in healthy adults, including an amplified RS/RA-specific antigen response, representing greater clonal unevenness. Unlike mature repertoires, however, there is more fluctuation in clonotype distribution, less clonotype stability, and more variable IFNy response of the M158-66 specific RS/RA clonotypes in JIA. This indicates that functional clonal expansion is altered in patients with JIA on immunosuppressive therapies. We propose that the response to the influenza M158-66 epitope described here is a general phenomenon for JIA patients receiving immunosuppressive therapy, and that the changes in clonal richness and unevenness indicate a retarded and uneven generation of a mature immune response. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Enteric defensins are essential regulators of intestinal microbial ecology

Author

Salzman, Nita H, Hung, Kuiechun, Haribhai, Dipica, Chu, Hiutung, Karlsson-Sjöberg, Jenny, Amir, Elad, Teggatz, Paul, Barman, Melissa, Hayward, Michael, Eastwood, Daniel, Stoel, Maaike, Zhou, Yanjiao, Sodergren, Erica, Weinstock, George M, Bevins, Charles L, Williams, Calvin B, and Bos, Nicolaas A

Subjects
Microbiology, Biological Sciences, Digestive Diseases, Vaccine Related, Aetiology, 2.1 Biological and endogenous factors, Animals, Bacteria, Colony Count, Microbial, Ecology, Female, Flow Cytometry, Humans, In Situ Hybridization, Fluorescence, Interleukin-17, Intestinal Mucosa, Intestine, Small, Intestines, Male, Matrix Metalloproteinase 7, Metagenome, Mice, Mice, Inbred Strains, Mice, Knockout, Mice, Transgenic, Microscopy, Fluorescence, Phylogeny, RNA, Ribosomal, 16S, T-Lymphocytes, Helper-Inducer, alpha-Defensins, Immunology, Biochemistry and cell biology
Abstract

Antimicrobial peptides are important effectors of innate immunity throughout the plant and animal kingdoms. In the mammalian small intestine, Paneth cell alpha-defensins are antimicrobial peptides that contribute to host defense against enteric pathogens. To determine if alpha-defensins also govern intestinal microbial ecology, we analyzed the intestinal microbiota of mice expressing a human alpha-defensin gene (DEFA5) and in mice lacking an enzyme required for the processing of mouse alpha-defensins. In these complementary models, we detected significant alpha-defensin-dependent changes in microbiota composition, but not in total bacterial numbers. Furthermore, DEFA5-expressing mice had striking losses of segmented filamentous bacteria and fewer interleukin 17 (IL-17)-producing lamina propria T cells. Our data ascribe a new homeostatic role to alpha-defensins in regulating the makeup of the commensal microbiota.

Published
2010

5. BATF is Required for Treg Homeostasis and Stability to Prevent Autoimmune Pathology

Author

Khatun, Achia, primary, Wu, Xiaopeng, additional, Qi, Fu, additional, Gai, Kexin, additional, Kharel, Arjun, additional, Kudek, Matthew R., additional, Fraser, Lisa, additional, Ceicko, Ashley, additional, Kasmani, Moujtaba Y., additional, Majnik, Amber, additional, Burns, Robert, additional, Chen, Yi‐Guang, additional, Salzman, Nita, additional, Taparowsky, Elizabeth J., additional, Fang, Dayu, additional, Williams, Calvin B., additional, and Cui, Weiguo, additional

Published
2023
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10. A colitogenic memory [CD4.sup.+] T cell population mediates gastrointestinal graft-versus-host disease

Author

Zhou, Vivian, Agle, Kimberle, Chen, Xiao, Beres, Amy, Komorowski, Richard, Belle, Ludovic, Taylor, Carolyn, Zhu, Fenlu, Haribhai, Dipica, Williams, Calvin B., Verbsky, James, Blumenschein, Wendy, Sadekova, Svetlana, Bowman, Eddie, Ballantyne, Christie, Weaver, Casey, Serody, David A., Vincent, Benjamin, Serody, Jonathan, Cua, Daniel J., and Drobyski, William R.

Subjects
Inflammation -- Research -- Risk factors, Integrins -- Health aspects -- Research -- Influence, Graft versus host reaction -- Research -- Care and treatment -- Complications and side effects, Health care industry
Abstract

Damage to the gastrointestinal tract is a major cause of morbidity and mortality in graft-versus-host disease (GVHD) and is attributable to T cell-mediated inflammation. In this work, we identified a unique [CD4.sup.+] T cell population that constitutively expresses the [β.sub.2] integrin CD11c and displays a biased central memory phenotype and memory T cell transcriptional profile, innate-like properties, and increased expression of the gut-homing molecules [α.sub.4][β.sub.7] and CCR9. Using several complementary murine GVHD models, we determined that adoptive transfer and early accumulation of [β.sub.2] integrin- expressing [CD4.sup.+] T cells in the gastrointestinal tract initiated Th1-mediated proinflammatory cytokine production, augmented pathological damage in the colon, and increased mortality. The pathogenic effect of this [CD4.sup.+] T cell population critically depended on coexpression of the IL-23 receptor, which was required for maximal inflammatory effects. Non-Foxp3-expressing [CD4.sup.+] T cells produced IL-10, which regulated colonic inflammation and attenuated lethality in the absence of functional [CD4.sup.+][Foxp3.sup.+] T cells. Thus, the coordinate expression of CD11c and the IL-23 receptor defines an IL-10-regulated, colitogenic memory [CD4.sup.+] T cell subset that is poised to initiate inflammation when there is loss of tolerance and breakdown of mucosal barriers., Introduction Graft-versus-host disease (GVHD) is a proinflammatory syndrome that is initiated by donor T cells and is the major complication of allogeneic hematopoietic stem cell transplantation (1-3). The overproduction of [...]

Published
2016
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17. Contributors

Author

Abman, Steven H., primary, Ahmed, Amina, additional, Allen, Marilee C., additional, Askenazi, David, additional, Back, Stephen A., additional, Baldwin, H. Scott, additional, Ballard, Roberta A., additional, Bancalari, Eduardo, additional, Bates, Carlton M., additional, Batisky, Donald L., additional, Baumgart, Stephen, additional, Benedetti, Thomas J., additional, Berry, Gerard T., additional, Bianchi, Diana W., additional, Binenbaum, Gil, additional, Bollepalli, Sureka, additional, Bonifacio, Sonia L., additional, Cairo, Mitchell S., additional, Campbell, Katherine H., additional, Caplan, Michael, additional, Cederbaum, Stephen, additional, Chandra, Sudhish, additional, Chen, Ming, additional, Claure, Nelson, additional, Clyman, Ronald I., additional, Cohen, Bernard A., additional, Cole, F. Sessions, additional, Copelovitch, Lawrence, additional, Cunningham, Michael, additional, de Alba Campomanes, Alejandra G., additional, Dees, Ellen, additional, Denne, Scott C., additional, Devaskar, Sherin U., additional, DiBlasi, Robert M., additional, Dimmitt, Reed A., additional, Eichenwald, Eric C., additional, Eisenstein, Eli M., additional, Evans, Jacquelyn R., additional, Evans, Kelly, additional, Farmer, Diana L., additional, Ferrieri, Patricia, additional, Ferriero, Donna M., additional, Finer, Neil N., additional, Fraga, Maria Victoria, additional, Furman, Lydia, additional, Furth, Susan, additional, Gauda, Estelle B., additional, Glader, Bertil, additional, Gleason, Christine A., additional, Goldberg, Michael J., additional, Gonzalez, Fernando, additional, Gopalani, Sameer, additional, Grant, P. Ellen, additional, Greene, Carol L., additional, Guevara-Gallardo, Salvador, additional, Guignard, Jean-Pierre, additional, Guttentag, Susan, additional, Haldeman-Englert, Chad R., additional, Hansen, Thomas, additional, Hing, Anne V., additional, Hohimer, A. Roger, additional, Hostetter, Margaret K., additional, Hull, Andrew D., additional, Jackson, J. Craig, additional, Jain, Lucky, additional, Jain, Vandana, additional, Janjua, Halima Saadia, additional, Juul, Sandra E., additional, Kalkunte, Satyan, additional, Kaplan, Bernard S., additional, Keller, Roberta L., additional, Kelly, Thomas F., additional, Kern, Steven E., additional, Kerkar, Nanda, additional, Kinsella, John P., additional, Kirsch, Roxanne, additional, Kleinman, Monica E., additional, Klitzner, Thomas S., additional, Lambert, Sarah M., additional, Lantos, John D., additional, Leone, Tina A., additional, Leppert, Mary, additional, Levy, Harvey L., additional, Lewin, Mark, additional, Lin-Su, Karen, additional, L. Loh, Mignon, additional, Lorch, Scott A., additional, Lugo, Ralph A., additional, Mai, Volker, additional, Marino, Bradley S., additional, Markovitz, Barry, additional, Marquard, Kerri, additional, Martin, Camilia R., additional, Martin, Richard J., additional, Matthay, Katherine K., additional, Matthews, Dana C., additional, Mayock, Dennis E., additional, Meadow, William L., additional, Menon, Ram K., additional, Mercuri, Eugenio, additional, Mohan, Sowmya S., additional, Moley, Kelle, additional, Mollen, Thomas J., additional, Moore, Jeremy P., additional, Moore, Thomas R., additional, Munson, David A., additional, Murray, Jeffrey C., additional, Neu, Josef, additional, New, Maria I., additional, Nguyen-Vermillion, Annie, additional, Niklas, Victoria, additional, Nimkarn, Saroj, additional, Padbury, James F., additional, Pane, Marika, additional, Paneth, Nigel, additional, Parker, Thomas A., additional, Patterson, Janna C., additional, Pettker, Christian M., additional, Plawner, Lauren L., additional, Poenaru, Dan, additional, Poindexter, Brenda B., additional, Posencheg, Michael A., additional, Prabhu, Sanjay P., additional, Püttgen, Katherine B., additional, Quinn, Graham E., additional, Raju, Tonse N.K., additional, Ramos, Gladys A., additional, Reinking, Benjamin E., additional, Richardson, C. Peter, additional, Rimoin, David L., additional, Robbins, Elizabeth, additional, Robertson, Richard L., additional, Rollins, Mark D., additional, Rose, Susan R., additional, Rosen, Mark A., additional, Rubin, Lewis P., additional, Sahai, Inderneel, additional, Saitta, Sulagna C., additional, Sánchez, Pablo J., additional, Satou, Gary M., additional, Schanler, Richard J., additional, Scher, Mark S., additional, Schleiss, Mark R., additional, Scholz, Thomas D., additional, Schwaderer, Andrew L., additional, Seri, Istvan, additional, Sharma, Surendra, additional, Shereck, Evan B., additional, Sibley, Eric, additional, Signore, Caroline, additional, Simmons, Rebecca, additional, Smith, Jeffrey B., additional, Smith, Lorie B., additional, Song, Clara, additional, Steinhorn, Robin H., additional, Suchy, Frederick J., additional, Sulyok, Endre, additional, Tarczy-Hornoch, Peter, additional, Taylor, George A., additional, Taylor, James A., additional, Thomas, Janet A., additional, Tiller, George E., additional, Tran, Mark M., additional, Trautman, Michael Stone, additional, Upperman, Jeffrey S., additional, van de Ven, Carmella, additional, Vernon, Margaret M., additional, Allan Walker, W., additional, Wallen, Linda D., additional, Waller, Sarah A., additional, Warady, Bradley A., additional, Ward, Robert M., additional, Watchko, Jon F., additional, Wernovsky, Gil, additional, White, Klane K., additional, Williams, Calvin B., additional, Woodrum, David, additional, Woodward, George A., additional, Wright, Dakara Rucker, additional, Wright, Jeffrey A., additional, Wright, Linda L., additional, Young, Christopher M., additional, Young, Guy, additional, Zackai, Elaine H., additional, and Zderic, Stephen A., additional

Published
2012
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22. Contributors

Author

Adams-Chapman, Ira, primary, Ades, Anne M., additional, Ahmed, Amina, additional, Albers, Simone, additional, Allen, Marilee C., additional, Andrew, Maureen, additional, Back, Stephen A., additional, Baldwin, H. Scott, additional, Ballard, Philip L., additional, Ballard, Roberta A., additional, Banks-Randall, Beverly A., additional, Baumgart, Stephen, additional, Beckerman, Karen P., additional, Benedetti, Thomas J., additional, Berry, Gerard T., additional, Berseth, Carol Lynn, additional, Bethin, Kathleen E., additional, Bianchi, Diana W., additional, Cairo, Mitchell S., additional, Caldamone, Anthony, additional, Chandra, Sudhish, additional, Chmait, Ramen, additional, Clyman, Ronald I., additional, Cohen, Bernard A., additional, Cohen, Meryl S., additional, Cohen, Mitchell I., additional, Cohn, Robert M., additional, Cole, F. Sessions, additional, Corbet, Anthony, additional, Denne, Scott C., additional, Di Maggio, Theresa J., additional, Eichenwald, Eric C., additional, Evans, Jacquelyn R., additional, Evans, Nick, additional, Fanaroff, Avroy A., additional, Ferriero, Donna M., additional, Fisher, Delbert A., additional, Flores-Sarnat, Laura, additional, Friedlich, Philippe S., additional, Gaynor, J. William, additional, Gest, Alfred L., additional, Geva, Tal, additional, Gibbons, Mary Ann E., additional, Gilbert, William M., additional, Glader, Bertil E., additional, Gleason, Christine A., additional, Goldberg, Michael J., additional, Good, William V., additional, Goodwin, Gregory, additional, Gopalani, Sameer, additional, Greene, Carol L., additional, Grottkau, Brian E., additional, Gruber, Peter J., additional, Guignard, Jean-Pierre, additional, Guttentag, Susan, additional, Hamrick, Shannon E.G., additional, Hansen, Thomas N., additional, Hostetter, Margaret K., additional, Hughes, Samuel C., additional, Hull, Andrew D., additional, Jedeikin, Roy, additional, Juul, Sandra E., additional, Kaplan, Bernard S., additional, Kaplan, Paige, additional, Kazin, Rebecca A., additional, Kelly, Thomas F., additional, Kuhle, Stefan, additional, Laing, Ian A., additional, Levy, Harvey L., additional, Loh, Mignon L., additional, Lorch, Scott A., additional, Lugo, Ralph A., additional, Machin, Geoffrey A., additional, MacMahon, James R., additional, Macones, George A., additional, Madan, Ashima, additional, Marino, Bradley S., additional, Martinez, Alma, additional, Maschoff, Kathryn L., additional, Massicotte, Patricia, additional, Matthay, Katherine K., additional, Mentzer, William C., additional, Merrill, Jeffrey D., additional, Miller, Carol A., additional, Mitchell, Lesley, additional, Moise, Alicia A., additional, Mollen, Thomas J., additional, Monahan, Timothy P., additional, Moore, Thomas R., additional, Muglia, Louis J., additional, Nelson, Robert M., additional, Newman, Thomas B., additional, Pallotto, Eugenia K., additional, Pan, Erica S., additional, Parravicini, Elvira, additional, Partridge, J. Colin, additional, Poenaru, Dan, additional, Poindexter, Brenda B., additional, Polin, Richard A., additional, Polk, Daniel H., additional, Pursley, DeWayne M., additional, Ramanathan, Rangasamy, additional, Ramierez-Schrempp, Daniela, additional, Regan, Joan A., additional, Richard, Elisabeth G., additional, Robertson, Richard L., additional, Rosen, Mark A., additional, Rubin, Lewis P., additional, Rychik, Jack, additional, Saitta, Sulagna C., additional, Sánchez, Pablo J., additional, Sarnat, Harvey B., additional, Schanler, Richard J., additional, Scher, Mark S., additional, Seri, Istvan, additional, Siegfried, Elaine C., additional, Silverman, Gary A., additional, Simmons, Rebecca, additional, Sniderman, Susan, additional, Spray, Thomas L., additional, Stanley, Charles A., additional, Stevenson, David K., additional, Stoll, Barbara J., additional, Taeusch, H. William, additional, Tarczy-Hornoch, Peter, additional, Taylor, George A., additional, Thomas, Janet A., additional, Tulassay, Tivadar, additional, van de Ven, Carmella, additional, Vohr, Betty R., additional, Ward, Robert M., additional, Weintrub, Peggy Sue, additional, Welty, Stephen, additional, Wernovsky, Gil, additional, Williams, Calvin B., additional, Wright, Linda L., additional, Young, Alison Z., additional, Zackai, Elaine H., additional, and Zderic, Stephen A., additional

Published
2005
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31. Serum S100A8/A9 and S100A12 Levels in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis: Relationship to Maintenance of Clinically Inactive Disease During Anti–Tumor Necrosis Factor Therapy and Occurrence of Disease Flare After Discontinuation of Therapy

Author

Hinze, Claas H., primary, Foell, Dirk, additional, Johnson, Anne L., additional, Spalding, Steven J., additional, Gottlieb, Beth S., additional, Morris, Paula W., additional, Kimura, Yukiko, additional, Onel, Karen, additional, Li, Suzanne C., additional, Grom, Alexei A., additional, Taylor, Janalee, additional, Brunner, Hermine I., additional, Huggins, Jennifer L., additional, Nocton, James J., additional, Haines, Kathleen A., additional, Edelheit, Barbara S., additional, Shishov, Michael, additional, Jung, Lawrence K., additional, Williams, Calvin B., additional, Tesher, Melissa S., additional, Costanzo, Denise M., additional, Zemel, Lawrence S., additional, Dare, Jason A., additional, Passo, Murray H., additional, Ede, Kaleo C., additional, Olson, Judyann C., additional, Cassidy, Elaine A., additional, Griffin, Thomas A., additional, Wagner‐Weiner, Linda, additional, Weiss, Jennifer E., additional, Vogler, Larry B., additional, Rouster‐Stevens, Kelly A., additional, Beukelman, Timothy, additional, Cron, Randy Q., additional, Kietz, Daniel, additional, Schikler, Kenneth, additional, Mehta, Jay, additional, Ting, Tracy V., additional, Verbsky, James W., additional, Eberhard, Anne B., additional, Huang, Bin, additional, Giannini, Edward H., additional, and Lovell, Daniel J., additional

Published
2019
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35. Risk, Timing, and Predictors of Disease Flare After Discontinuation of Anti-Tumor Necrosis Factor Therapy in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis With Clinically Inactive Disease

Author

Lovell, Daniel J., primary, Johnson, Anne L., additional, Huang, Bin, additional, Gottlieb, Beth S., additional, Morris, Paula W., additional, Kimura, Yukiko, additional, Onel, Karen, additional, Li, Suzanne C., additional, Grom, Alexei A., additional, Taylor, Janalee, additional, Brunner, Hermine I., additional, Huggins, Jennifer L., additional, Nocton, James J., additional, Haines, Kathleen A., additional, Edelheit, Barbara S., additional, Shishov, Michael, additional, Jung, Lawrence K., additional, Williams, Calvin B., additional, Tesher, Melissa S., additional, Costanzo, Denise M., additional, Zemel, Lawrence S., additional, Dare, Jason A., additional, Passo, Murray H., additional, Ede, Kaleo C., additional, Olson, Judyann C., additional, Cassidy, Elaine A., additional, Griffin, Thomas A., additional, Wagner-Weiner, Linda, additional, Weiss, Jennifer E., additional, Vogler, Larry B., additional, Rouster-Stevens, Kelly A., additional, Beukelman, Timothy, additional, Cron, Randy Q., additional, Kietz, Daniel, additional, Schikler, Kenneth, additional, Schmidt, Kara M., additional, Mehta, Jay, additional, Wahezi, Dawn M., additional, Ting, Tracy V., additional, Verbsky, James W., additional, Eberhard, B. Anne, additional, Spalding, Steven, additional, Chen, Chen, additional, and Giannini, Edward H., additional

Published
2018
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38. Development of functionally distinct Treg subsets in the thymus

Author

Owen, David L., primary, Mahmud, Shawn A, additional, Williams, Jason B, additional, Jeschke, Jonathan C, additional, Aggarwal, Praful, additional, Broeckel, Ulrich, additional, Alegre, Marisa, additional, Zheng, Ye, additional, Williams, Calvin B, additional, and Farrar, Michael A, additional

Published
2017
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39. TGF-β1 along with other platelet contents augments Treg cells to suppress anti-FVIII immune responses in hemophilia A mice

Author

Haribhai, Dipica, primary, Luo, Xiaofeng, additional, Chen, Juan, additional, Jia, Shuang, additional, Shi, Linzheng, additional, Schroeder, Jocelyn A., additional, Weiler, Hartmut, additional, Aster, Richard H., additional, Hessner, Martin J., additional, Hu, Jianda, additional, Williams, Calvin B., additional, and Shi, Qizhen, additional

Published
2016
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45. IL-10 produced by iTreg cells controls colitis and pathogenic ex-iTreg cells during immunotherapy1

Author

Schmitt, Erica G., Haribhai, Dipica, Williams, Jason B., Aggarwal, Praful, Jia, Shuang, Charbonnier, Louis-Marie, Yan, Ke, Lorier, Rachel, Turner, Amy, Ziegelbauer, Jennifer, Georgiev, Peter, Simpson, Pippa, Salzman, Nita H., Hessner, Martin J., Broeckel, Ulrich, Chatila, Talal A., and Williams, Calvin B.

Subjects
Mice, Knockout, Mice, Inbred BALB C, Recombinant Fusion Proteins, Cell Differentiation, Forkhead Transcription Factors, Mice, Transgenic, Colitis, Inflammatory Bowel Diseases, T-Lymphocytes, Regulatory, Article, Interleukin-10, Disease Models, Animal, Mice, Mutagenesis, Insertional, Animals, Newborn, Immune Tolerance, Animals, Transcriptome
Abstract

“Natural” regulatory T (nTreg) cells that express the transcription factor Foxp3 and produce IL-10 are required for systemic immunological tolerance. “Induced” Treg (iTreg) cells are non-redundant and essential for tolerance at mucosal surfaces, yet their mechanisms of suppression and stability are unknown. We investigated the role of iTreg cell-produced IL-10 and iTreg cell fate in a treatment model of inflammatory bowel disease. Colitis was induced in Rag1−/− mice by the adoptive transfer of naïve CD4+ T cells carrying a non-functional Foxp3 allele. At the onset of weight loss, mice were treated with both iTreg and nTreg cells where one marked subset was selectively IL-10-deficient. Body weight assessment, histological scoring, cytokine analysis, and flow cytometry were used to monitor disease activity. Transcriptional profiling and TCR repertoire analysis were used to track cell fate. When nTreg cells were present but IL-10 deficient, iTreg cell-produced IL-10 was necessary and sufficient for the treatment of disease, and vice versa. Invariably, ~85% of the transferred iTreg cells lost Foxp3 expression (ex-iTreg) but retained a portion of the iTreg transcriptome, which failed to limit their pathogenic potential upon retransfer. TCR repertoire analysis revealed no clonal relationships between iTreg and ex-iTreg cells, either within mice or between mice treated with the same cells. These data identify a dynamic IL-10-dependent functional reciprocity between Treg subsets that maintains mucosal tolerance. The niche supporting stable iTreg cells is limited and readily saturated, which promotes a large population of ex-iTreg cells with pathogenic potential during immunotherapy.

Published
2012

46. The T cell receptor repertoires of regulatory and conventional T cells specific for the same foreign antigen are distinct1

Author

Relland, Lance M., Williams, Jason B., Relland, Gwendolyn N., Haribhai, Dipica, Ziegelbauer, Jennifer, Yassai, Maryam, Gorski, Jack, and Williams, Calvin B.

Subjects
Mice, Knockout, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, Receptors, Antigen, T-Cell, Epitopes, T-Lymphocyte, chemical and pharmacologic phenomena, Mice, Transgenic, Gene Rearrangement, T-Lymphocyte, T-Lymphocytes, Regulatory, Article, Mice, Inbred C57BL, Mice, Mice, Inbred AKR, Animals, Cells, Cultured
Abstract

The relationship between the TCR repertoires of natural regulatory T (nTreg) and conventional T (Tconv) cells capable of responding to the same antigenic epitope is unknown. Here, we used TCRβ-chain transgenic mice to generate polyclonal nTreg and Tconv cell populations specific for a foreign antigen. CD4+ T cells from immunized 3.L2β+/− TCRα+/− Foxp3EGFP mice were re-stimulated in culture to yield nTreg cells (EGFP+) and Tconv cells (EGFP−) defined by their antigenic reactivity. Relative to Tconv cells, nTreg cell expansion was delayed, although a higher proportion of viable nTreg cells had divided after 72 hours. Spectratype analysis revealed that both the nTreg and Tconv cell responses were different and characterized by skewed distributions of CDR3 lengths. CDR3 sequences from nTreg cells displayed a divergent pattern of Jα usage, minimal CDR3 overlap (3.4%), and less diversity than CDR3 sequences derived from Tconv cells. These data indicate that foreign antigen-specific nTreg and Tconv cells are clonally distinct, and that foreign antigen-specific nTreg cells populations are constrained by a limited TCR repertoire.

Published
2012

48. A Central Role for Induced Regulatory T Cells in Tolerance Induction in Experimental Colitis1

Author

Haribhai, Dipica, Lin, Wen, Edwards, Brandon, Ziegelbauer, Jennifer, Salzman, Nita H., Carlson, Marc R., Li, Shun-Hwa, Simpson, Pippa M., Chatila, Talal A., and Williams, Calvin B.

Subjects
Male, Mice, Knockout, Mice, Inbred BALB C, Cell Survival, Green Fluorescent Proteins, Cell Differentiation, Forkhead Transcription Factors, Mice, Transgenic, Colitis, Adoptive Transfer, T-Lymphocytes, Regulatory, Article, Disease Models, Animal, Mice, Immune Tolerance, Animals, Promoter Regions, Genetic, Cells, Cultured
Abstract

In addition to thymus-derived or natural T regulatory (nT(reg)) cells, a second subset of induced T regulatory (iT(reg)) cells arises de novo from conventional CD4(+) T cells in the periphery. The function of iT(reg) cells in tolerance was examined in a CD45RB(high)CD4(+) T cell transfer model of colitis. In situ-generated iT(reg) cells were similar to nT(reg) cells in their capacity to suppress T cell proliferation in vitro and their absence in vivo accelerated bowel disease. Treatment with nT(reg) cells resolved the colitis, but only when iT(reg) cells were also present. Although iT(reg) cells required Foxp3 for suppressive activity and phenotypic stability, their gene expression profile was distinct from the established nT(reg) "genetic signature," indicative of developmental and possibly mechanistic differences. These results identified a functional role for iT(reg) cells in vivo and demonstrated that both iT(reg) and nT(reg) cells can act in concert to maintain tolerance.

Published
2009

49. Affinity-based Selection of Regulatory T Cells Occurs Independent of Agonist-mediated Induction of Foxp3 Expression1

Author

Relland, Lance M., Mishra, Manoj K., Haribhai, Dipica, Edwards, Brandon, Ziegelbauer, Jennifer, and Williams, Calvin B.

Subjects
Stem Cells, Receptors, Antigen, T-Cell, Cell Differentiation, Forkhead Transcription Factors, Mice, Transgenic, Thymus Gland, Ligands, T-Lymphocytes, Regulatory, Article, Immunity, Innate, Peptide Fragments, Mice, Inbred C57BL, Hemoglobins, Mice, Mice, Inbred AKR, Organ Culture Techniques, Transforming Growth Factor beta, Cell Adhesion, Animals
Abstract

Natural regulatory T (nT(reg)) cells recognize self-peptides with high affinity, yet the understanding of how affinity influences their selection in the thymus is incomplete. We use altered peptide ligands in transgenic mice and in organ culture to create thymic environments spanning a broad range of ligand affinity. We demonstrate that the nT(reg) TCR repertoire is shaped by affinity-based selection, similar to conventional T cells. The effect of each ligand on the two populations is distinct, consistent with early nT(reg) cell lineage specification. Foxp3 expression is an independent process that does not rely on "high affinity" binding per se, but requires a high-potency agonistic interaction for its induction. The timing of ligand exposure, TGFbeta signaling, and the organization of the thymic architecture are also important. The development of nT(reg) cells is therefore a multistep process in which ligand affinity, potency, and timing of presentation all play a role in determining cell fate.

Published
2009

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