The healthy immune system depends upon a balance of proliferation and death of white blood cells, including T cells, to contain and eliminate infectious pathogens effectively without doing unintended damage to self tissues. One way that activated T cells are instructed to die occurs upon repeated engagement of the T cell receptor (TCR); a process known as restimulation-induced cell death (RICD). This self-regulatory death program protects against excessive expansion of T cells as an immune response unfolds. The long-term objective of this project is to define specific biochemical signals that convert the TCR signal from proliferation and survival to death, which to date remain poorly understood. We previously discovered a novel RICD defect in T cells from patients with X-linked lymphoproliferative disease (XLP), which lack expression of SLAM-associated protein (SAP). SAP, in conjunction with the SLAM family receptor protein NTB-A, is required for proper RICD in normal T cells. Using a variety of genetic and biochemical approaches in human cells, this project aims to further elucidate and manipulate the molecular mechanism by which SAP and NTB-A direct TCR signaling for death in activated T cells. This basic research will illuminate a previously unrecognized network of biochemical signals connecting SAP, NTB-A, and key kinases (e.g. LCK, DGKa), phosphatases (SHP-1), and transcription factors (FOXP3) that ultimately govern RICD sensitivity in conventional and regulatory T cells. Moreover, our proposed survey of numerous human donors will determine if and how SAP and NTB-A are meaningful biomarkers of RICD sensitivity in normal individuals, which could provide an innovative new diagnostic tool for predicting the magnitude of T cell responses to infection or vaccination. Elucidating these critical signaling events will improve our basic understanding of abnormal T cell signaling and cell death in patients with lymphoproliferative and autoimmune disorders beyond XLP. Targeting these molecular interactions should offer a new therapeutic approach to control T cell responses by manipulating RICD sensitivity. Such a strategy could be applied to numerous clinical contexts in which culling excess T cells (e.g. autoimmunity, lymphoproliferative disease) or boosting T cell responses (e.g. infection, cancer) could help ameliorate disease.

Public Health Relevance

The proposed research will further elucidate new biochemical pathways involved in regulating T cell death, focusing on the function of two molecules with potential diagnostic value in dictating the magnitude of a given T cell response. Defining these pathways will help us better understand, predict, and potentially control immune responses in situations where increasing (e.g. chronic infections, tumor elimination) or decreasing (e.g. autoimmunity) T cell numbers would be beneficial. Therefore, this research is broadly relevant to public health and numerous clinical settings in which the potency of the T cell-directed immune response is directly related to disease severity and outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM105821-01A1S1
Application #
9277078
Study Section
Program Officer
Marino, Pamela
Project Start
2015-09-15
Project End
2020-07-31
Budget Start
2015-09-15
Budget End
2016-07-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
Katz, Gil; Voss, Kelsey; Yan, Toria F et al. (2018) FOXP3 renders activated human regulatory T cells resistant to restimulation-induced cell death by suppressing SAP expression. Cell Immunol 327:54-61
Snow, Andrew L; Larsen, Sasha E (2017) Different death destinies: relative apoptosis sensitivity shapes the human effector CD8+ T-cell response derived from distinct memory subsets. Cell Death Dis 8:e3030
Voss, Kelsey; Larsen, Sasha E; Snow, Andrew L (2017) Metabolic reprogramming and apoptosis sensitivity: Defining the contours of a T cell response. Cancer Lett 408:190-196
Larsen, Sasha E; Bilenkin, Abegail; Tarasenko, Tatiana N et al. (2017) Sensitivity to Restimulation-Induced Cell Death Is Linked to Glycolytic Metabolism in Human T Cells. J Immunol 198:147-155
Larsen, Sasha E; Voss, Kelsey; Laing, Eric D et al. (2017) Differential cytokine withdrawal-induced death sensitivity of effector T cells derived from distinct human CD8+ memory subsets. Cell Death Discov 3:17031
Ma, Chi A; Stinson, Jeffrey R; Zhang, Yuan et al. (2017) Germline hypomorphic CARD11 mutations in severe atopic disease. Nat Genet 49:1192-1201
Ruffo, Elisa; Malacarne, Valeria; Larsen, Sasha E et al. (2016) Inhibition of diacylglycerol kinase ? restores restimulation-induced cell death and reduces immunopathology in XLP-1. Sci Transl Med 8:321ra7