T cells in Immunity and Autoimmunity.
Four research projects that focus on the biology of T cells and their role in immunity and autoimmunity are being pursued in my laboratory.
The first, concerns investigation of the mechanism by which myelin-reactive T cells develop, why these cells are activated and cause the autoimmune disease multiple sclerosis (MS) in certain individuals but not others and how we can control these cells and reverse the disease. The investigation uses an animal model of human MS known as experimental allergic encephalomyelitis (EAE).
The second project concerns another autoimmune disease known as insulin-dependent diabetes mellitus. T cells specific for b cell-associated antigens seem to be responsible for mediating destruction of insulin-producing b cells of the islets of Langerhans. We are investigating the mechanism of diabetogenesis and trying to define approaches for modulation of the autoreactive T cells and delay of the onset of diabetes in the non-obese diabetic (NOD) mouse model. Both the first and second research programs share the long-term objective of developing antigen specific therapies against autoimmunity.
The third projects concerns the mechanism by which T cells develop into memory. Our investigation is aimed at understanding how initial events upon activation of T cells control the memory pathway. More specifically, we are trying to determine whether cell division is a key factor in the development of memory. This project should yield information useful for the development of vaccines which rely on the generation of memory cells.
The fourth project is aimed at understanding how the newborn is susceptible to microbial infections and allergic reactions. It is believed that immune responses in the neonate lack Th1 cells, the main mediators of immune defense against infections, while the dominant Th2 lymphocytes are the principal mediator of allergic reactions. Our aim is to delineate the mechanism by which neonatal immunity lacks Th1 cells and are biased towards Th2. Recently, we identified a new heteroreceptor that is specifically expressed on developing Th1 cells and utilized by IL-4 of the Th2 mates to drive apoptosis of the Th1 lymphocytes to skew neonatal immunity towards Th2. Understanding how the heteroreceptor signals apoptosis and immunocompromise the newborn should shed light on the function of the immune system of the newborn and yield knowledge useful for the development of pediatric vaccines and suppression of allergic reactions.
Wan, X., and H. Zaghouani. 2014. Antigen-specific therapy against type 1 diabetes: Mechanisms and perspectives. Immunotherapy 6:155-164.
Dhakal. M*., J. C. Hardaway*, F. B. Guloglu, M.M. Miller, C. M. Hoeman, A. A. Zaghouani, X. Wan, L. M.Rowland, J. A. Cascio, M. P. Sherman, and H. Zaghouani. 2014. IL-13Rα1 is a surface marker for M2 macrophages influencing their differentiation and function. Eur. J. Immunol. In press. *These authors contributed equally to the publication. 44:842-855.
Cascio, J. A., M-T. Khairallah, X. Wan, W. Chen, L. M. Rowland, M. Dhakal, M. M. Miller, and H. Zaghouani. 2014. In trans T cell tolerance exacerbates experimental allergic encephalomyelitis by interfering with protective antibody responses. J. Neuroimmunol. 266:49-55.
Wan, X., F. B. Guloglu, A. M. VanMorlan, L. M. Rowland, S. Zaghouani, J.A. Cascio, M. Dhakal, C. M. Hoeman, and H. Zaghouani. 2013. Recovery from Overt Type 1 Diabetes Ensues When Immune Tolerance and β Cell Formation Are Coupled with Regeneration of Endothelial Cells in the Pancreatic Islets. Diabetes. 62:2879-2889.
Guloglu, F.B., J. S. Ellis, X. Wan, M. Dhakal, C. M. Hoeman, C. L. Haymaker, J. A. Cascio and H. Zaghouani. 2013. Antigen-Free Adjuvant Assists Late Effector CD4 T Cells to Transit to Memory in Lymphopenic Hosts. J. Immunol. 191:1126-1135.
Cascio, J.A., C. L. Haymaker, R. D. Divekar, S. Zaghouani, M-T. Khairallah, X. Wan, L. M. Rowland, M. Dhakal, W. Chen & H. Zaghouani. 2013. Antigen-specific effector CD4 T lymphocytes school lamina propria dendritic cells to transfer innate tolerance. J. Immunol. 190:6004-6014.
Hoeman, C.M., M. Dhakal, A. A. Zaghouani, J. A. Cascio, X. Wan, M-T Khairallah, W. Chen and H. Zaghouani. 2013. Developmental Expression of IL-12Rβ2 on Naïve Neonatal T Cells Counters the Up-Regulation of IL-13Rα1 on Primary Th1 Cells and Balances Immunity in the Newborn. J. Immunol. 190:6155-6163.
Wan. X,F. Betul Guloglu, A. M. VanMorlan, L. M. Rowland, R. Jain, C. L. Haymaker,J. A. Cascio, M. Dhakal, C. M. Hoeman, D. M. Tartar, and H. Zaghouani. 2012. Mechanisms Underlying Antigen-Specific Tolerance of Stable and Convertible Th17 Cells During Suppression of Autoimmune Diabetes. Diabetes 61:2054-2065.
Haymaker, C.L., F.B. Guloglu, J.A. Cascio, J.C. Hardaway, M. Dhakal, X. Wan, C.M. Hoeman, S. Zaghouani, L.M. Rowland, D.M. Tartar, A.M. VanMorlan, and H. Zaghouani. 2012. Bone marrow derived IL-13α1-posibite early thymic progenitors are restricted to the myeloid lineage. J. Immunol. doi:10.4049/jimunol.1103316.
Divekar, R. D., C. L. Haymaker, J. A. Cascio, B. F. Guloglu, J. S. Ellis, D. M. Tartar, C. M. Hoeman, C. L. Franklin, B. H. Zinselmeyer, J. N. Lynch, M. J. Miller and H. Zaghouani. 2011. T Cell Dynamics During Induction of Tolerance and Suppression of Experimental Allergic Encephalomyelitis. J. Immunol. 187:3979-3986
Lee, S.-M., H. Yang, D. M. Tartar, B. Gao, X. Luo, S. Q. Ye, H. Zaghouani, and D. Fang. 2011. Prevention and treatment of diabetes with resveratrol in a non-obese mouse model of type 1 diabetes. Diabetologia 54:1136-1146.
Zaghouani, H. 2011. Born without immunity. International Innovation, Disseminating science, research and technology. International Innovation 10: 66-68.
Ellis, J. S., F. B. Guloglu, D. M. Tartar, C. M. Hoeman, C. L. Haymaker, J. A. Cascio, X. Wan, M. Dhakal, A. VanMorlan, S-H Yahng, and H. Zaghouani. 2010. Antigen Presenting Cells Expressing High Levels of PD-L2 Sustain the Development of CD4-T Cell Memory. J. Immunol. 185:3149-3157.
Hoeman, C. M., M. Dhakal, and H. Zaghouani. 2010. Overcoming Dendritic Cell Tardiness to Triumph over IL-13 Receptor: A Strategy for the Development of Effective Pediatric Vaccines. Discovery Medicine 9: 554-559.
Tartar, D.M., A. VanMorlan, X. Wan, B. F. Guloglu, R. Jain, C. L. Haymaker, J.S. Ellis, C.M. Hoeman, J. A. Cascio, M. Dhakal, M. Oukka, and H. Zaghouani. 2010. FoxP3+RORgt+ T helper intermediates display suppressive function against autoimmune diabetes. J. Immunol. 184: 3377-3385.
Zaghouani, H., C. M. Hoeman, and B. Adkins. 2009. Neonatal immunity: Faulty T-helpers and shortcomings of dendritic cells. Trends. Immunol. 30:585-591.
Zhang, J., S-M. Lee, S. Shannon, B. Gao, A. Chen, R. Divekar, M. McBurney, H. Braley-Mullen, H. Zaghouani and D. Fang. 2009. Sirt1, a type III histone deacetylase is essential for maintenance of T cell tolerance. J. Clin. Invest. 119:3048-3058.
Tartar, D.M., A. VanMorlan, and H. Zaghouani. 2009. Tregs/Th17 cells: Promiscuous Signals and Fear of Commitment? Immunotherapy. 1: 27-29.
Dai Y. D., I. G. Marrero, P. Gros, H. Zaghouani, L. S. Wicker, and E. E. Sercarz. 2009. SLC11a1 enhances the autoimmune diabetogenic T-cell response by altering processing and presentation of pancreatic islet antigens. Diabetes. 58:156-164.
Lee, H-H*., C.M. Hoeman*, J. C. Hardaway, F. B. Guloglu, J. S. Ellis, R. Jain, R. Divekar, D. M. Tartar, C. L. Haymaker, and H. Zaghouani. 2008. Delayed maturation of an IL-12-producing dendritic cell subset explains the early Th2 bias in neonatal immunity. J. Exp. Med.205(10):2269-2280. *Co-first authors.
Yu. P., C. L. Haymaker, R. D. Divekar, J. S. Ellis, J. C. Hardaway, R. Jain, D. M. Tartar, C.M. Hoeman, J. A. Cascio, A. Ostermeier and H. Zaghouani. 2008. Fetal exposure to high avidity T cell receptor ligand enhances expansion of peripheral T regulatory cells. J. Immunol. 181:73-80.
Jain, R., D. M. Tartar, R. K. Gregg, R. D. Divekar, J. J. Bell, H-Hee Lee, P. Yu, J. S. Ellis, C. M. Hoeman, C. L. Franklin, and H. Zaghouani. 2008. Innocuous IFNg induced by adjuvant-free antigen restores normoglycemia In non-obese diabetic (NOD) mice through inhibition of IL-17 production. J. Exp. Med. 205(1):207-18.
Bell, J. J., R. D. Divekar, J. S. Ellis, J. A. Cascio, C. L. Haymaker, R. Jain, D. M. Tartar, C. M. Hoeman, J. C. Hardaway, and H. Zaghouani. 2008. In Trans T Cell Tolerance Diminishes Autoantibody Responses and Exacerbates Experimental Allergic Encephalomyelitis. J. Immunol. 180(3):1508-16.
Bell, J.J., J.S. Ellis, F.B. Guloglu, D.M. Tartar, H-H. Lee, R. D. Divekar, R. Jain, P. Yu, C.M. Hoeman,and H. Zaghouani. 2008. Early Effector T Cells Producing Significant IFNg Develop into Memory. J. Immunol. 180:179-187.
Bot, A., D. Smith, B. Phillips, S. Bot, C. Bona and H. Zaghouani. 2006. Immunologic control of tumors by in vivo FcgR-targeted antigen loading in conjunction with dsRNA-mediated immune modulation. J. Immunol. 176:1363-1374.
Caprio-Young, J., J.J. Bell, H-H. Lee, J.S. Ellis, D.M. Nast, G. Sayler, B. Min and H. Zaghouani. 2006. Neonatally Primed Lymph Node but not Splenic T Cells Display a Gly-Gly Motif Withing the T Cell Receptor Beta Chain Complementarity Determining Region 3 (CDR3) That Controls Affinity and may affect Lymphoid Organ Retention. J. Immunol. 176:357-364.
Phillips, W.D., D. J. Smith, C.A. Bona, A. Bot, and H. Zaghouani. 2005. Recombinant immunoglobulin-based epitope delivery: a novel class of autoimmune regulators. Int Rev Immunol. 24:501-517.
Yu. P., R. K. Gregg, J. J. Bell, J. S. Ellis, R. Divekar, H-H. Lee, R. Jain, H. Waldner, J. C. Hardaway, M. Collins, V. K. Kuchroo, and H. Zaghouani. 2005. Specific T regulatory cells (Tregs) display broad suppressive functions against experimental allergic encephalomyelitis upon activation with cognate antigen. J. Immunol.174(11):6772-6780.
Gregg, R. K., J. J. Bell, H-H. Lee, R. Jain, S. J. Schoenleber, R. Divekar, and H. Zaghouani 2005. IL-10 diminishes CTLA-4 expression on islet-resident T cells and sustains their activation rather than tolerance. J. Immunol. 174:662-70.
Gregg, R. K., R. Jain, S. J. Schoenleber, R. Divekar, J. J. Bell, H-H. Lee, Yu P. and H. Zaghouani 2004. A sudden decline in active membrane-bound TGFb impairs both T regulatory cell function and protection against autoimmune diabetes. J. Immunol. 173:7308-7316.
Li L, HH Lee, JJ Bell, RK Gregg, JS Ellis, A Gessner and H Zaghouani. 2004. IL-4 Utilizes an Alternative Receptor to Drive Apoptosis of Th1 Cells and Skews Neonatal Immunity toward Th2. Immunity 20:429-440.
Bell, J. J., B. Min, R. K. Gregg, H-H. Lee, and H. Zaghouani. 2003. Break of Neonatal Th1 Tolerance and Exacerbation of Experimental Allergic Encephalomyelitis by Interference with B7 Costimulation. J. Immunol. 171:1801-1808.
Legge, KL, RK Gregg, R Maldonado-Lopez, L Li, JC Caprio, M Moser, and H Zaghouani. 2002. On the role of dendritic cells in peripheral T cell tolerance and modulation of autoimmunity. J. Exp. Med. 196:217-227.
Pack CD, AE Cestra, B Min, KL Legge, L Li, JC Caprio, JJ Bell, RK Gregg, and H Zaghouani. 2001. Neonatal exposure to antigen primes the immune system to develop responses in various lymphoid organs and promotes bystander regulation of diverse T cell specificities. J. Immunol. 167:4187-4195.
Li L, KL Legge, B Min, JJ Bell, R Gregg, J Caprio and H Zaghouani. 2001. Neonatal immunity develops in a transgenic TCR transfer model and reveals a requirement for elevated cell input to achieve organ-specific responses. J. Immunol. 167:2585-2594.
Legge KL, Bell J, L Li, R Gregg, JC Caprio, and H Zaghouani. 2001. Multi-modal antigen specific therapy for autoimmunity. Inter. Rev. Immunol. 20:593-611.
Min B, KL Legge, JJ Bell, L Li, JC Caprio, RK Gregg and H Zaghouani. 2001. Neonatal exposure to antigen induces a defective CD40 ligand expression that undermines both IL-12 production aby antigen presenting cells and IL-2 receptor up-regulation on splenic T cells and perpetuates IFNg – dependent T cell anergy. J. Immunol. 166:5594-5603.
Legge KL, B Min, JC Caprio, L Li, RK Gregg, JJ Bell and H Zaghouani. 2000. Coupling of peripheral tolerance to endogenous IL-10 promotes effective modulation of myelin-activated T cells and ameriorates experimental allergic encephalomyelitis. J. Exp. Med. 191:2039-2051.
Anderson AC, LB Nicholson, KL Legge, V Turchin, H Zaghouani, VK Kuchroo. 2000. High frequency of auto-reactive myelin proteolipid protein (PLP)-specific T cells in the periphery of naïve mice: mechanisms of selection of the self-reactive repertoire. J. Exp. Med. 191:761-770.
Min B, KL Legge, JC Caprio, L Li, R Gregg and H Zaghouani. 2000. Differential control of neonatal tolerance by antigen dose versus extended exposure and adjuvant. Cell. Immunol. 200:45-55.
Min B, KL Legge, L Li, JC Caprio, CD Pack, R Gregg, D McGavin, D Slauson, and H Zaghouani. 2000. Neonatal tolerant immunity for vaccination against autoimmunity. Intern. Rev. Immunol. 19:247-264.