MICaB Graduate Program
Main navigation |
Dan Kaplan, M.D., Ph.D.
Langerhans & Dendritic Cells of the Skin
Unlike antigen introduced systemically, the development of immune responses against antigen at barrier surfaces is relatively poorly studied. It is clear, however, that tissue resident dendritic cells (DC) play a central role. They are capable of acquiring antigen and migrating to regional lymph node (LN) where they activate T cells and thereby initiate adaptive immune responses. Commensal organisms at barrier sites, however, are tolerated by the immune system. Since antigens from these organisms are not present in the thymus where central tolerance is established, responses against commensal organisms are limited through the development of peripheral tolerance. This process is incompletely understood, but appears to rely on specialized DC sub-populations that actively inhibit antigen-specific T cell responses in the regional LN.
The lab’s focus is the early events after antigen exposure in the skin that allows for the development of appropriate immune responses to pathogens while limiting responses directed against commensal organisms. We are concentrating on two opposing dendritic cell (DC) subsets in the skin. We have previously shown that DC in the epidermis (the outermost layer of skin), termed Langerhans cells (LC) suppress the development of skin immune responses while DC that reside deeper in the skin, dermal DC, are required for the development of skin immune responses. This is consistent with a model in which LC specialize in limiting effector responses against commensal organisms. According to this model, antigen found exclusively in the epidermis is presented by LC leading to no response or tolerance and thereby prevents deleterious immune responses against commensal organisms. For invasive pathogens which penetrates through the epidermis, antigen is present in both the epidermis and dermis. In this situation antigen is acquired by both dermal DC which are responsible for the generation of effector responses, and by epidermal LC which inhibit that response.
We have engineered mice that have either constitutive or inducible depletion of LC. We have also employed Cre-lox systems to constitutively or inducibly ablate genes of interest selectively in LC. By combining these unique strains of mice with models of skin inflammation such as allergic contact dermatitis and infection, we are able to examine the function of Langerhans cells and the molecular mechanisms underlying these functions.
Selected Recent Publications:
- Ryan, C., C. L. Leonardi, J. G. Krueger, A. B. Kimball, B. E. Strober, K. B. Gordon, R. G. Langley, J. A. de Lemos, Y. Daoud, D. Blankenship, S. Kazi, D. H. Kaplan, V. E. Friedewald, and A. Menter. 2011. Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: a meta-analysis of randomized controlled trials. JAMA 306:864-871.
- Igyarto, B. Z., K. Haley, D. Ortner, A. Bobr, M. Gerami-Nejad, B. T. Edelson, S. M. Zurawski, B. Malissen, G. Zurawski, J. Berman, and D. H. Kaplan. 2011. Skin-resident murine dendritic cell subsets promote distinct and opposing antigen-specific T helper cell responses. Immunity 35:260-272.
- Kastenmuller, K., U. Wille-Reece, R. W. Lindsay, L. R. Trager, P. A. Darrah, B. J. Flynn, M. R. Becker, M. C. Udey, B. E. Clausen, B. Z. Igyarto, D. H. Kaplan, W. Kastenmuller, R. N. Germain, and R. A. Seder. 2011. Protective T cell immunity in mice following protein-TLR7/8 agonist-conjugate immunization requires aggregation, type I IFN, and multiple DC subsets. J Clin Invest 121:1782-1796.
- Taveirne, S., V. De Colvenaer, T. Van Den Broeck, E. Van Ammel, C. L. Bennett, T. Taghon, B. Vandekerckhove, J. Plum, B. E. Clausen, D. H. Kaplan, and G. Leclercq. 2011. Langerhans cells are not required for epidermal Vgamma3 T cell homeostasis and function. J Leukoc Biol 90:61-68.
- Hattori, T., S. K. Chauhan, H. Lee, H. Ueno, R. Dana, D. H. Kaplan, and D. R. Saban. 2011. Characterization of Langerin-expressing dendritic cell subsets in the normal cornea. Invest Ophthalmol Vis Sci 52:4598-4604.
- Teichmann, L. L., M. L. Ols, M. Kashgarian, B. Reizis, D. H. Kaplan, and M. J. Shlomchik. 2010. Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity 33:967-978.
- Kaplan, D. H. 2010. Langerhans cells: not your average dendritic cell. Trends Immunol 31:437.
- Kaplan, D. H. 2010. In vivo function of Langerhans cells and dermal dendritic cells. Trends Immunol 31:446-451.
- Li, H., D. H. Kaplan, C. Matte-Martone, H. S. Tan, S. Venkatesan, K. Johnson, A. J. Demetris, J. McNiff, M. J. Shlomchik, and W. D. Shlomchik. 2011. Langerhans cells are not required for graft-versus-host disease. Blood 117:697-707.
- Bobr, A., I. Olvera-Gomez, B. Z. Igyarto, K. M. Haley, K. A. Hogquist, and D. H. Kaplan. 2010. Acute ablation of Langerhans cells enhances skin immune responses. J Immunol 185:4724-4728.
- Igyarto, B. Z., and D. H. Kaplan. 2010. The evolving function of Langerhans cells in adaptive skin immunity. Immunol Cell Biol 88:361-365.
- Igyarto, B. Z., M. C. Jenison, J. C. Dudda, A. Roers, W. Muller, P. A. Koni, D. J. Campbell, M. J. Shlomchik, and D. H. Kaplan. 2009. Langerhans cells suppress contact hypersensitivity responses via cognate CD4 interaction and langerhans cell-derived IL-10. J Immunol 183:5085-5093.
- Nestle, F.O., Kaplan, D.H., Barker, J. 2009 “Psoriasis.” New England Journal of Medicine. 361(5):496-509.
- Vesely D.L., Fish. D, Shlomchik M.J., Kaplan D.H., Bockenstedt LK. 2009. “Langerhans Cell Deficiency Impairs Ixodes scapularis Suppression of Th1 Responses in Mice”, Infection and Immunity, 77:5; 1881-1887.
- Kaplan, D.H., Kissenpfennig A., Clausen B.E., 2008. “Insights into Langerhans Cell function from LC ablation models” Eur. J. Immunol.,38:9; 2369-76.
- Obhrai, J.S., Oberbarnscheidt, M., Zhang N., Mueller D.L., Shlomchik, W.D., Lakkis, F.G., Shlomchik, M.J., Kaplan, D.H. 2008. “Langerhans Cells Are Not Required For Efficient Skin Graft Rejection” J. Invest. Dermatology, 128:1950-1955.
- Strid, J., Roberts S.J., Filler, R.B., Lewis, J.M., Kwong, B.Y., Schpero W., Kaplan, D.H., Hayday A.C., Girardi, M. 2008. “NKG2D-ligand upregulation promoted rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis.” Nature Immunology. 9:146-154.
- Bursch, L.S., Wang, L., Igyarto, B., Kissenpfennig, A., Maslissen B., Kaplan, D.H., Hoqguist K.A. 2007, “Identification of a Novel Population of Langerhans Cells” J. Exp. Med. 204:3147-56.
- McNiff, J.M., Kaplan, D.H. 2007 “Plasmacytoid Dendritic Cells are Present in Cutaneous Dermatomyositis Lesions in a Pattern Distinct from Lupus Erythematosus” J. Cutan. Pathol.35(5):452-6
- Kaplan, D.H., Jenison, M.D., Li, M.O., Flavell, R.A., Shlomchik, M.J. 2007 “Autocrine TGFb is required for Langerhans Cell Development.” J Exp Med. 204:2545-52.
- Kaplan D.H., Jenison, M.C., Shlomchik W.D., Shlomchik M.J. 2005 “Langerhans Cell Deficient Mice Develop Enhanced Contact Hypersensitivitiy”. Immunity 23:611-620.
- Kaplan D.H., Anderson B.E., Shlomchik W.D., Shlomchik M.J. 2004 “Tissues affected by graft-versus-host disease vary with MHC haplotype in MHC-matched, MiHA-incompatable murine models”. J Immunol 173:5467-5475.