HSCI Alumni: Thomas S. Kupper, MD
Dana-Farber Cancer Institute
Harvard Medical School
Our laboratory is interested in how immune responses in skin are initiated, and how T cell mediated memory responses occur in skin, and in particular a newly described population of antigen experienced T cells known as Resident Memory T Cell (TRM). We have recently demonstrated that after vaccinia virus infection of epidermis, different populations of CD8+ effector T cells are generated in lymph nodes draining the site of infection. One population of effector memory T cells (TEM) acquire E and P selectin ligands, CCR4 and other specific chemokine receptors, and rapidly home to skin, entering infected skin more readily than normal skin. In parallel, populations of central memory T cells (TCM) are generated. Most of these cells circulate between blood and distant lymph nodes, and some enter these lymph nodes and differentiate into TEM that home to distal sites. By 10 days after infection, CD8+ T cells are seen in skin (skin homing TEM), lymph nodes (TCM), and peripheral epithelial tissues such as lung, liver and gut (TEM, organ homing). These T cells persist in tissues as TRM and maintain their skin specific phenotype for > 6 months. Moreover, these TRM are alone (i.e., without the contribution of antibodies or TCM) sufficient to protect against subsequent skin infection. Interestingly, long term immunity to vaccinia is mediated largely by T cells, and B cells (and antibody) are dispensible. Studies in human skin have identified large numbers of TRM in normal human skin. We have begun to understand these TRM antigens through the skin interface with the environment. Remarkably, there are twice as many T cells in skin as in blood at steady state, and nearly 95% of all skin homing TEM actually reside in skin at any given time. At steady state, and in the absence of inflammation, epidermal Langerhans Cells appear to constitutively activate skin resident Tregs, while when inflammation and antigen are present, LC can activate skin resident TEM. Murine studies using parabiotic mice demonstrate that antigen specific skin resident TEM do not re-circulate into blood; thus, skin is a reservoir of TRM, poised to be activated by innate immune signals and foreign antigen, typically with pathogens previously encountered through skin. These findings have profound and novel implications for vaccine therapy, which at present is largely geared towards generating and optimal protective circulating antibody (i.e., humoral) response. Our results suggest that vaccines should be optimized so as to lead to deposition and accumulation of TRM in peripheral epithelial tissues, where subsequent pathogen encounter might be expected. This hypothesis is being tested as part of our Transformative Research Award (TR01) first funded in 2011. Immunizing with the goal of generating protective immunity as manifested by tissue resident TEM, at the epithelial interface most likely to be infected by the vaccine pathogen is a major goal of the laboratory. These same observations are relevant in vaccine development in the realm of cancer as well as infectious diseases. In addition to the above translational research studies,
Dr. Kupper sees patients with Cutaneous T Cell Lymphoma, subtypes of which represent malignancies of skin homing TEM and skin homing TCM. We recently reported that the anti-CD52 antibody alemtuzumab (Campath) can be highly effective in leukemic CTCL (TCM) but is completely inactive in mycosis fungoides CTCL (TEM). Developing novel therapies for CTCL based upon the biology of these transformed T cells is another goal of the laboratory. Finally, the study of tumor immunity as it applies to CTCL, as well as melanoma, Merkel cell carcinoma, and other skin malignancies, is a major focus of the laboratory.