Terri Marilyn Laufer, M.D.
3620 Hamilton Walk
Philadelphia, PA 19104
Fax: (215) 573-7599
Princeton University, 1983.
M.D. (College of Physicians and Surgeons)
Columbia University, 1987.
Description of Research ExpertiseResearch Interests
Thymic development and peripheral activation of autoreactive T cells; Requirements for tissue-specific expression of MHC class II molecules.
T cell development, autoimmunity, transgenesis, MHC class II function.
A transgenic approach is utilized to examine the immunologic sequelae of limiting MHC class II expression to subpopulations of professional antigen presenting cells, i.e. thymic epithelium, B cells, or dendritic cells. Cellular and molecular techniques including adoptive transfers, proliferation assays, and flow cytometric analysis are performed to understand the development of CD4+ T cells and the specificity and function of those T cells.
Major histocomatibility complex (MHC) class II molecules are required for the normal development in the thymus of CD4+ T cells and function to present peptide antigens to those CD4 cells in the periphery.
The distribution of class II molecules is limited to thymic epithelial cells-where they are required for the positive and negative selection of CD4+ T cells-and in the periphery where they are required for the survival and activation of those T cells. We have developed a series of transgenic mice with restricted expression of the MHC class II molecule, I-Ab, and used them to investigate the requirement for different populations of antigen presenting cells in the thymic selection, peripheral activation, and tolerance of CD4+ T cells. Our most well studied model is the K14 mouse in which MHC molecules are restricted to thymic cortical epithelium-both thymic medullary epithelium and bone marrow-derived cells are class II negative. Positive selection of CD4+ T cells does occur in the K14 thymus; however, clonal deletion of autoreactive thymocytes can not be detected. Thus, K14 CD4 cells proliferate to I-Ab-positive APC in vitro and cause graft-versus-host disease when injected into MHC-identical hosts. Our current studies are directed toward understanding the peptide specificity, function, and pathologic potential of these autoreactive T cells:
1) Examination of a series of K14-derived autoreactive T hybridomas demonstrates that the autoreactive population of CD4 cells is polyclonal; however, we are beginning to identify the individual peptides responsible for stimulating the autoreactive response. To better understand the thymic selection processes in both K14 and wildtype thymi, we have also derived TCR transgenics from two of the hybrids and have begun to analyze the thymic development and peripheral function of autoreactive TCR transgenic CD4+ T cells in both K14 and wildtype mice of various haplotypes, including NOD, the diabetogenic genotype.
2) Development of autoimmunity: Adoptive transfer systems are being utilized to tease apart the T cell and target-organ abnormalities that must be present to initiate an autoimmune disease. Disease models include graft-versus-host disease, Herpes simplex keratitis, and Type I diabetes.
3) Requirement for MHC class II in other antigen presenting populations. Our newest transgenics utilize the mb-1 and CD11c promoters to reexpress class II molecules in the B cells and dendritic cells, respectively, of class II-deficient mice. Studies will be directed towards understanding how limiting the expression of Class II molecules alters the positive and negative selection, peripheral survival, and peripheral survival and effector function of CD4+ T cells.
Selected PublicationsBarnett Burton E, Ciocca Maria L, Goenka Radhika, Barnett Lisa G, Wu Junmin, Laufer Terri M, Burkhardt Janis K, Cancro Michael P, Reiner Steven L: Asymmetric B cell division in the germinal center reaction. Science (New York, N.Y.) 335(6066): 342-4, Jan 2012.
Goenka R, Barnett LG, Silver JS, O'Neill PJ, Hunter CA, Cancro MP, Laufer TM.: Cutting edge: dendritic cell-restricted antigen presentation initiates the follicular helper T cell program but cannot complete ultimate effector differentiation. J Immunol. 187(3): 1091-5, Aug 2011 Notes: Epub 2011 Jun 29.
Wu GF, Corbo E, Schmidt M, Smith-Garvin JE, Matthew J Riese, Jordan MS, Laufer TM, Brown EJ, Maltzman JS.: Conditional deletion of SLP-76 in mature T cells abrogates peripheral immune responses. Eur J Immunol. Page: doi: 10.1002/eji.201040809, Apr 2011 Notes: [Epub ahead of print]
Wu GF, Shindler KS, Allenspach EJ, Stephen TL, Thomas HL, Mikesell RJ, Cross AH, Laufer TM.: Limited sufficiency of antigen presentation by dendritic cells in models of central nervous system autoimmunity. J Autoimmun. Page: [Epub ahead of print] Nov 2010.
Shaffer MH, Huang Y, Corbo E, Wu GF, Velez M, Choi JK, Saotome I, Cannon JL, McClatchey AI, Sperling AI, Maltzman JS, Oliver PM, Bhandoola A, Laufer TM, Burkhardt JK.: Ezrin is highly expressed in early thymocytes, but dispensable for T cell development in mice. PLoS One. 5(8): e12404, Aug 2010.
Laufer TM.: Inflammatory arthritis--an exciting confluence of human and animal research. Immunol Rev. 233(1): 5-8, Jan 2010.
Stephen TL, Tikhonova A, Riberdy JM, Laufer TM.: The activation threshold of CD4+ T cells is defined by TCR/peptide-MHC class II interactions in the thymic medulla. J Immunol. 183(9): 5554-62, Nov 2009.
Naiqian N, Laufer TM, Homer RJ, Cohn L.: Cutting edge: Limiting MHC class II expression to dendritic cells alters the ability to develop Th2- dependent allergic airway inflammation. J Immunol. 183: 1523-7, Jul 2009.
Sokol CL, Chu NQ, Yu S, Nish SA, Laufer TM, Medzhitov R.: Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat Immunol. 10(7): 713-20, Jul 2009 Notes: Epub 2009 May 4.
Perrigoue JG, Saenz SA, Siracusa MC, Allenspach EJ, Taylor BC, Giacomin PR, Nair MG, Du Y, Zaph C, van Rooijen N, Comeau MR, Pearce EJ, Laufer T M, Artis D.: MHC class II-dependent basophil-CD4+ T cell interactions promote T(H)2 cytokine-dependent immunity. Nat Immunol. 10(7): 697-705, Jul 2009 Notes: Epub 2009 May 24.