Program Director/Principal Investigator (Last, First, Middle): Croft, Michael 2 R01 AI042944-10A2 PROJECT SUMMARY/ABSTRACT 4-1BB (CD137), a member of the TNFR superfamily, strongly influences immune cell function in many inflammatory situations. 4-1BB was originally described as a costimulatory molecule and binding to its known ligand, 4-1BBL, a member of the TNF family, is thought to enhance immune responses and the cross-talk between T cells and APC. However, recent data have suggested that 4-1BB biology is much more complex, and that 4-1BB can also play a regulatory or negative role during immune responses. With 4-1BB-deficient mice and using T cells that cannot express 4-1BB, we have found that the initial role, and perhaps its primary role, is an inhibitory rather than stimulatory action. The absence of 4-1BB, in gene-deficient animals, leads to deregulated dendritic cell (DC) development;enhanced responsiveness of T cells to specific antigen;and spontaneous inflammation and autoimmune-type symptoms that develop with age. The molecular basis of these inhibitory activities are unknown. We have found that suppression of myelopoiesis and DC differentiation is due to 4-1BBL delivering inhibitory signals to bone marrow progenitor cells. We also hypothesize that 4-1BB signaling to peripheral T cells can generate both effector cells and regulatory T cells depending on the context in which these signals are received. The studies in this grant will investigate how 4-1BB exerts its modulatory actions through bidirectional cross-talk with 4-1BBL that regulate T cell responsiveness to antigen and hematopoiesis. We will determine how 4-1BB interacting with 4-1BBL controls myeloid and monocyte progenitors that lead to dendritic cell development, and how 4-1BB and 4-1BBL interactions modulate the balance between effector and regulatory T cells that may contribute to maintenance of tolerance and prevention of autoimmune disease.
4-1BB and its ligand(s) are expressed on the surface of many immune cells and are thought to regulate the ability to mount an immune response. 4-1BB provides essential signals to a T cell to allow it to continue dividing late in its response, and to suppress excessive death. However, 4-1BB interactions also act as a rate- limiting step to control initial T cell division and expansion as well as development of dendritic cells. By understanding where and when 4-1BB and its ligand(s) are expressed, and the functional importance of these putative interactions, we will gain knowledge that might lead to ways to either enhance or suppress T cell responses, and so might be therapeutically relevant in a number of disease settings such as in limiting autoimmunity, or augmenting the ability to respond to cancerous cells or infectious pathogens.
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