T-cell dependent immunity against antigens is heterogeneous with respect to the cytokines made by the CD4+ T helper cells (Th cells), and the isotypes of antibodies secreted by the B cells. The type of Th response is critical in determining the clinical outcome of various disease processes. Thus a number of diseases result from a skewing of Th1 to Th2 responses (HIV, allergy), or Th2 to Th1 responses (organ-specific autoimmunity). A deep understanding of Th responses, and the ability to redirect such responses in vivo, may provide attractive strategies for immunotherapy against such diseases. While it is known that the cytokines produced early in a response are crucial in determining the Th polarization of the response, the cell types that initiate the Th polarization in vivo are unknown. The present proposal seeks to understand the roles played by dendritic cells (DCs) in this process. In mice DCs can be classified into the lymphoid and myeloid families. Our recent work has revealed an exquisite role for distinct DC subsets in determining the polarity of immune response in vivo. Thus lymphoid DCs promote Th1 differentiation, and myeloid DCs elicit Th2 cytokines. In this context, the present proposal investigates the role(s) that these DC subsets play in polarizing Th responses in vivo, and their ability to redirect ongoing Th responses.
Our specific Aims can be summarized as follows: (1) Can repeated stimulations of T cells in vivo with a given DC subset engender increasing polarization to the Th1 or Th2 pathway? (2) Can the Th phenotypes elicited in vivo by the DC subsets be altered by restimulation with DCs of the opposite phenotype? (3) To determine whether injecting antigen-pulsed myeloid DCs can redirect pathogenic Th1 responses towards benign Th2 responses in a mouse model of autoimmune diabetes. (4) To determine the mechanism of IL-4 induction by myeloid DC'S. This research will provide us with a deeper understanding of DCs in the control of Th responses in vivo. It should also ultimately permit more effective use of DCs for the immunotherapy of autoimmunity and infectious diseases.
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