Date of Award

2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Jonathan S. Maltzman

Abstract

Signaling through the TCR governs all aspects of T cell biology, directing development, activation, division, and effector function. The SH2-domain-containing phosphoprotein of 76 kDa (SLP-76) is an adaptor protein integral to TCR signaling, and loss in cell lines abrogates the molecular complexes necessary for signal transduction. Deletion of SLP-76 in the germline or in developing thymocytes causes selection defects. Our lab has developed a system of timed deletion of SLP-76 in mature T cells to bypass any developmental defects and study its requirement in peripheral TCR signaling. Loss of SLP-76 in mature T cells does not alter cell surface phenotype, but prevents antigenic TCR signaling. This deletion model was used to determine the contribution of SLP-76 to TCR:self-peptideMHC ("tonic") signaling, which is vital for naïve cell survival. Loss of SLP-76 from peripheral T cells results in loss of naïve CD4+ and CD8+ T cells with kinetics consistent with other models of "tonic" signal abrogation.

CD4+ memory T cells utilize a combination of homeostatic division and increased life span to persist, through use of both "tonic" TCR and IL-7 signaling. CD44 marks two populations of memory cells, antigen-specific (AgSp) and memory phenotype (MP), which have distinct requirements for their persistence. MP cells can be further subdivided based on their rate of division, with fast-dividing cells requiring "tonic" signaling for turnover. Loss of SLP-76 prevents division of these fast-dividing cells, and reduces their persistence. Like fast-dividing MP cells, loss of SLP-76 affects the ability of AgSp cells to incorporate BrdU and transmit functional signals. In contrast to fast-dividing cells, numbers of AgSp cells are unaffected in the absence of SLP-76, persisting for greater than 30 weeks following deletion. Independent maintenance of a population of AgSp memory cells in the absence of normal homeostatic division suggests that the rate of death changes based on the division rate. By separating the determinants of division, survival, and maintenance of function, the studies presented here will direct cytokine- and "tonic"-based therapeutic approaches for promoting long-term immunity. Future studies in "tonic" signaling should be aimed at maintenance of function and not survival of AgSp populations.

Files over 3MB may be slow to open. For best results, right-click and select "save as..."

Share

COinS