The failure of T cell tolerance can lead to spontaneous inflammation and at worst autoimmune disease. The control of T cell tolerance versus immunity in part relies on signals from co-stimulatory and co-inhibitory receptors that control various activities of T cells. 4-1BB (CD137, ILA, TNFRSF9), a member of the tumor-necrosis factor receptor (TNFR) super-family, was originally identified as an inducible co-stimulatory molecule on activated T cells. The ligand of 4-1BB (4-1BBL, TNFSF9), a member of the TNF super-family, expressed on activated APC binds to 4-1BB that is induced on T cells, generating positive signals inside T cells to help them function and to augment various aspects of immunity. In contrast we have found an inhibitory role for 4-1BB that does not rely on interaction with 4-1BBL. The absence of 4-1BB, in gene-deficient animals, leads to an enhanced rather than suppressed responsiveness of T cells to specific antigen, and 4-1BB-deficient mice spontaneously generate autoimmune-type phenotypes with chronic inflammation at the mucosal interfaces, a phenotype not seen in 4-1BBL-deficient mice. Our hypothesis is that 4-1BB binds with unidentified ligands that are constitutively expressed or induced early in an immune response to limit T cell reactivity and maintain tolerance, but by switching partners to 4-1BBL expressed later with inflammation, 4-1BB can then provide a positive stimulatory action. Our preliminary results have identified both galectin-3 and galectin-9, two reported suppressive molecules, as partners for 4- 1BB. The studies in this grant will investigate the interaction of galectins with 4-1BB and determine whether 4-1BB/galectin interactions account for 4-1BB negatively regulating T cell responsiveness. The identification and characterization of novel binding partners for 4-1BB will provide new understanding into 4-1BB biology as well as T cell tolerance and chronic inflammation.

Public Health Relevance

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. 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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Transplantation, Tolerance, and Tumor Immunology (TTT)
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Lapham, Cheryl K
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La Jolla Institute
La Jolla
United States
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