Lymphocyte and Dendritic Cell Trafficking
An essential component of effective immune response targeting is the expression of specific lymphocyte trafficking programs. Eugene Butcher and his colleagues were the first to propose the combinatorial model of multi-step leukocyte trafficking and have shown that lymphocyte trafficking is determined by the association and sequential operation of adhesion and chemoattractant receptors that control the multi-step processes of lymphocyte homing, chemotactic navigation, and cell-cell interactions within tissues.
Mechanisms of Lymphocyte Trafficking
Dr. Butcher's group identified many of the molecular players involved and showed that these mechanisms direct immune effector and memory cells in a tissue-, microenvironment and lymphocyte subset-selective fashion, and are major determinants of the function of specialized immune cells in vivo. They have also shown that tumor cells express many of these receptors and has correlated tissue-specific homing receptor expression with tissue selective presentation and metastasis of, for example, epidermotrophic T cell neoplasms, and follicular and chronic lymphocytic lymphoid malignancies in man and of clonal lymphomas and leukemias in mouse models.
Plasmacytoid DCs
More recently, the Butcher lab has identified a polypeptide chemoattractant selective for plasmacytoid dendritic cells, a key immune cell implicated both in innate and adaptive immunity. Plasmacytoid DCs have been postulated to play a varied role in tumor immunity, and may have the ability to either induce or suppress tumor responses. Interestingly, the novel attractant is activated by proteases associated with tissue injury and tumor metastasis.
Specialized Trafficking Programs
Future studies of the Butcher lab will be directed at:
- defining specialized trafficking programs that characterize and help define functionally distinct subsets of circulating immune cells in blood, including effector and memory T and B cells, antibody secreting cells, dendritic cells, and macrophages implicated in tumor immunity;
- characterizing the specialized homing and functional properties of tissue infiltrating leukocytes involved in local immune, autoimmune and regulatory responses, including tumor infiltrating cells;
- defining the role of novel chemoattractants and receptors in lymphocyte and DC homing;
- characterizing the role of selected vascular and leukocyte homing and trafficking programs in DC and lymphocyte localization to tumors; and use of specific lymphocyte and DC recruitment mechanisms.
Trial Administration