In a healthy individual, the immune system uses several different immune tolerance mechanisms in order to prevent the development of autoimmune disease. For T cells, these include thymic and peripheral mechanisms that result in elimination of autoreactive cells, such as receptor editing and deletion, as well as other mechanisms that allow T cells with potentially autoreactive T cell receptors (TCR) to remain as part of the TCR repertoire but to be controlled in their ability to respond. The latter include inhibitory mechanisms that act intrinsically to the cell, generally referred to as anergy;and mechanisms that regulate extrinsically, through the activity of regulatory T cells. Little is known about the underlying mechanism responsible for whether a self-reactive CD8 T cell in the periphery undergoes tolerance through deletion or anergy. Studies in this proposal will delineate the molecular pathways through which peripheral tolerance of na?ve CD8 cells occurs.
Aim 1 will test the hypothesis that T cell receptor affinity determines whether tolerance occurs through anergy or deletion. The affinity of CD8 T cell activation will be varied using well-defined altered peptide ligands. We will also determine whether the tolerance mechanism induced through T cell recognition of antigen on cross-presenting dendritic cells in vivo depends upon the strength of TCR signaling. Preliminary data obtained through microarray analysis of gene expression in cells undergoing deletion and anergy has revealed a number of transcriptional features unique to each tolerance mechanism that form the basis for Aims 2 and 3 in this proposal.
Aim 2 will examine the molecular pathways that are responsible for T cell deletion. We will test the hypothesis that deletion occurs as the result of induction of the tumor suppressors genes, GADD45g and FHIT. These may contribute to activation of the proapoptotic Bim through stress induced MAP kinases. This will be tested by inactivating the components of these pathways through the use of genetically deficient mice and pharmacological inhibitors.
Aim 3 will test the hypothesis that the mechanism of anergy that occurs when na?ve CD8 cells are activated with a high dose of toleragen involves enhanced expression of one or more negative costimulatory molecules, including;PD-1, NKG2a and Semaphorin 7A.
Understanding and enforcing immune tolerance mechanisms is important in preventing autoimmune diseases and in preventing graft rejection. The goal of this proposal is to further our understanding of molecular mechanisms that underlie immune tolerance so that we may develop new drugs and interventions that will help to prevent these diseases.
|Smith, Trevor; Lin, Xiaotian; Mello, Marielle et al. (2017) Peripheral Deletion of CD8 T Cells Requires p38 MAPK in Cross-Presenting Dendritic Cells. J Immunol 199:2713-2720|
|Lin, Wai W; Yi, Zuoan; Stunz, Laura L et al. (2015) The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development. Sci Signal 8:ra88|
|Maine, Christian J; Marquardt, Kristi; Scatizzi, John C et al. (2015) The effect of the autoimmunity-associated gene, PTPN22, on a BXSB-derived model of lupus. Clin Immunol 156:65-73|
|Smith, Trevor R F; Verdeil, Gregory; Marquardt, Kristi et al. (2014) Contribution of TCR signaling strength to CD8+ T cell peripheral tolerance mechanisms. J Immunol 193:3409-16|
|Maine, Christian J; Marquardt, Kristi; Cheung, Jocelyn et al. (2014) PTPN22 controls the germinal center by influencing the numbers and activity of T follicular helper cells. J Immunol 192:1415-24|
|Redmond, William L; Wei, Cheng-Hong; Kreuwel, Huub T C et al. (2008) The apoptotic pathway contributing to the deletion of naive CD8 T cells during the induction of peripheral tolerance to a cross-presented self-antigen. J Immunol 180:5275-82|
|Wong, S B Justin; Bos, Rinke; Sherman, Linda A (2008) Tumor-specific CD4+ T cells render the tumor environment permissive for infiltration by low-avidity CD8+ T cells. J Immunol 180:3122-31|
|Wei, Cheng-Hong; Sherman, Linda A (2007) N-terminal trimer extension of nominal CD8 T cell epitopes is sufficient to promote cross-presentation to cognate CD8 T cells in vivo. J Immunol 179:8280-6|
|Redmond, William L; Sherman, Linda A (2005) Peripheral tolerance of CD8 T lymphocytes. Immunity 22:275-84|
|Redmond, William L; Marincek, Boris C; Sherman, Linda A (2005) Distinct requirements for deletion versus anergy during CD8 T cell peripheral tolerance in vivo. J Immunol 174:2046-53|
Showing the most recent 10 out of 26 publications