Our laboratory is interested in how immune responses occur in epithelial interfaces with the environment, principally skin. Epidermis, the outermost layer of skin, is a reservoir of IL-1a, and its release after injury recruits leukocytes to skin. Skin is also home to different classes of dendritic cells, bearing various TLR’s, which link the innate and adaptive immune systems. Skin also contains large numbers of memory effector T cells that bear skin homing molecules. These molecules, including Cutaneous Lymphocyte Antigen (CLA, an E selectin ligand) and CCR4, are present on virtually all skin resident T cells, which are otherwise diverse with respect to cytokine profile and effector function.
Immunization through skin, including cutaneous vaccination, generates populations of antigen specific skin homing T cells. This occurs during the naïve to memory transition in skin draining lymph nodes. Upregulation of skin homing vs. gut homing molecules (which occurs in LN draining gut) is a result of distinct genetic programs driven by the respective microenvironments of the lymph nodes draining those tissues. Though distinct sets of dendritic cells are important, other unidentified microenvironment factors are at least as critical.
Very recently, a class of T cells that produces IL-17, but not IL-4 or IFNg, has been identified. This distinct lineage of cells, which include both CD4 (Th17) and CD8 (Tc17) subsets, is generated by combinations of TGFb, IL-1, TNFa, and IL-6. They appear to use IL-21 as an autocrine growth factor and IL-23 as a paracrine growth factor. Teleologically, IL-17 producing T cells are generated to protect the host from extracellular pathogens. They are central to skin host defense, and it is becoming clear that many immunologically mediated skin diseases involve Th17 cells (e.g., psoriasis).
Skin cancers are the most common human cancers. Malignancies of epidermal keratinocytes are often curable by topical immunotherapy, destruction, or excision. Exceptions include squamous cell carcinomas in immunosuppressed patients and Merkel cell carcinomas, both of which are frequently deadly. Melanoma is an aggressive skin cancer, with tumors as thin as 3 mm or less often metastasizing. Metastatic melanoma is uniformly fatal, but like other skin cancers is a potential target for immunotherapy. We are employing lessons from skin immunology to develop a new generation of cancer vaccines, as well as an approach to adoptive immunotherapy for cancer using populations of T cells with appropriate homing and effector properties.
An additional area of focus in the laboratory is Cutaneous T Cell Lymphoma (CTCL), which is a malignancy of the skin homing T cell. The incidence of CTCL has tripled in the past 20 years, and patients with this disease are seen at our DFCI clinic, and substantial translational research on basic biology, etiology, and treatment of this skin lymphoma are another central focus of the Kupper lab.
|
References:
- Shin J, Monti S, Aires DJ, Duvic M, Golub T, Jones DA, Kupper TS. Lesional gene expression profiling in cutaneous T cell lymphoma reveals natural clusters associated with disease outcome. Blood. 2007 Jul 16; [Epub ahead of print]
- Liu L, Fuhlbrigge RC, Karibian K, Tian T, Kupper TS.Dynamic programming of CD8+ T cell trafficking after live viral immunization. Immunity. 2006 Sep;25(3):511-20.
- Clark RA, Kupper TS.IL-15 and dermal fibroblasts induce proliferation of natural regulatory T cells isolated from human skin. Blood. 2007 Jan 1;109(1):194-202.
- Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K, Dowgiert RK, Kupper TS. The vast majority of CLA+ T cells are resident in normal skin. J Immunol. 2006 Apr 1;176(7):4431-9.
|
Harvard University Home / GSAS Home / HMS Home 
