Age-Dependent CD7 Functions in T Cell Responses

About This Grant

PROJECT ABSTRACT Over the course of aging, the immune system undergoes changes that impair responsiveness to challenges such as of viral infection and cancer, maladies that require a sufficient responsive from cytotoxic CD8 T cells. CD8 T cells reflect the broadly observed weakening of immunity and such, the age-associated sub- optimal activation and dysfunction of CD8 T cells permits the often-lethal persistence of viral infection and cancer. T cell activation, differentiation, and effector function are regulated by T cell receptor (TCR) signaling, which are modulated be by various signaling networks. One notable group of modifiers are transmembrane protein such as CD28 as their extracellular domain can be targeted through monoclonal antibody therapeutics. While the broad networks associated with the TCR and adaptor-modulated signals have been elucidated for some time, there is currently a paucity in identification of novel druggable targets that can alter CD8 T cell outcome. To improve T cell-targeted therapeutics, especially in susceptible populations like the elderly, it is paramount to expand our knowledge regarding TCR-associated signaling networks. We propose to define the novel ligand-independent role for transmembrane costimulatory receptor CD7 in modulating TCR signaling and determine how CD7- mediated signals helps direct CD8 T cell activation, differentiation, and function. Notably CD7 expression declines with age in parallel with diminished immune responsiveness. We hypothesize that the loss of CD7-modulated TCR signaling is a major contributor to the reduced responsiveness to immune challenge observed in aging adults. To address this hypothesis, in Aim I, we will determine how reduced CD7 expression in aged CD8 T cells influences TCR signaling and contributes to hyporesponsiveness. We will first assess the differences in TCR signal initiation and propagation through targeted analysis of critical signaling axes in naturally arising murine CD7+, CD7–, and engineered CD7KO T cells. To complement these findings, we will additionally perform unbiased mass spectrometry- based phosphoproteomic characterization of the kinase signaling that occurs in TCR engagement in the presence and absence of CD7. In Aim II, we will determine the functional consequences of loss of CD7 in anti-viral T cell responses. We will assess differences in activation, differentiation, and function among CD7+, CD7–, or CD7KO CD8 T cells in response to acute LCMV infection by flow cytometry as well as single cell RNA sequencing. Sufficiency for ectopic expression of CD7 to rescue diminished anti-viral responses in naturally occurring CD7– will also be tested. Our long-term goal is to understand how CD7 functions to direct T cell fate function over the course of aging, then utilize these discoveries to help develop novel immunomodulatory therapies. Upon completion, we believe these findings will positively impact the field by expanding our mechanistic understanding of a novel therapeutic target that programs T cell fate and function to reprogram diminished immune responses later in life.