Immunology Program Research Focuses

The Immunology Program has targeted the fields of cancer, and autoimmune and infectious diseases as areas of major focus for its research effort. The group’s main interests focus primarily on the roles of cells and soluble factors that regulate innate immunity and the transition to adaptive immune responses. Our primary research is directed toward understanding mechanisms of activation of the Dendritic Cells (DCs) critical for the induction of primary immune responses.

Another area of interest is natural killer T (NKT) cells. DCs constitute a unique system of cells able to induce primary immune responses. We are studying the basic mechanisms that underlie DC differentiation and developing fundamentally new strategies to manipulate their functions. The remarkable immunostimulatory property of DCs resides in their ability to efficiently capture and subsequently present antigens to T cells in an optimal costimulatory context. This function is possible because DCs exist in different functional and maturation stages. Immature DCs reside within nonlymphoid tissues, where they actively capture and process antigen. Contact with proinflammatory cytokines and bacterial products induces DC maturation. Upon activation, DCs migrate to secondary lymphoid tissues, such as the lymph nodes, where they reside as potent stimulators of naïve T cells. This well-defined maturation pathway is subsequently modulated during DC–T cell interaction, involving a combination of signals resulting from the interaction of costimulatory molecules as well as the production of cytokines. Maturation of DCs is triggered by pathogens, viruses, and inflammatory stimuli such as cytokines. Signals such as lipopolysaccharide (LPS), tumor necrosis factor-a (TNF-a),and CD40-L stimulate development of mature DCs defined by a well-characterized surface phenotype and effector profile (IL-12 production) that results intype 1 helper T cell (Th1) priming function. However, these are not the only stimuli to which DCs respond. Recently, nonconventional stimuli have been shown to induce DC maturation, giving rise to mature DCs of various phenotypes and functions. In the presence of factors such as prostaglandins or vitamin D, mature DCs will secrete IL-10, thereby priming Th2 differentiation.

NKT cells constitute a unique subpopulation of T lymphocytes that is highly conserved in both human and murine species. NKT cells express some NK-specific surface markers, such as the C-type lectin NKRP-1A, thereby sharing some properties with classical NK cells. However, the most reliable marker to consistently identify this subset is their peculiar T cell receptor (TCR). NKT cells are characterized by the usage of a highly homogenous TCR, consisting in humans of an invariant Va24JaQ rearrangement paired preferentially with a variable Vb11 chain. In the mouse, NKT cells express an invariant Va14Ja281 rearrangement paired with variable Vb8, Vb7, or Vb2. In terms of co-receptor expression, NKT cells belong either to the single positive CD4+ or the double negative CD4-CD8-TCRa/b+ subset of lymphocytes. Although natural ligands of NKT cells have not yet been identified, these cells are activated when their TCR recognizes glycosylceramides derived from marine sponges, presented by CD1d. Although this class of a-glycosylated ceramides is not readily detectable in mammals, they should share critical structural features with natural CD1d-ligands, suggesting that NKT cells recognize antigens containing a hydrophobic (lipid) and a hydrophilic moiety. NKT cells have characteristic effector functions and secrete large amounts of both interferon–g (IFN-g) and interleukin-4 (IL-4) upon activation. NKT cells are known to mediate IL-12-induced tumor rejection in liver and lung cancer, and studies have shown that upon activation a-GalCer, they are highly cytotoxic, produce high levels of IF-g, and activate DCs for IL-12 production.

The goal of our group is to reach a deep understanding of innate immunity to allow us to manipulate it and utilize it as an important adjuvant therapy for cancer, autoimmune diseases and vaccines.

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       Last Updated Jun 15, 2006