Micrornas Regulate the Balance of Terminal Effector and Memory Lineages During Cd8 T Cell Expansion.

Open Access
Author:
Baumann, Florian Martin
Graduate Program:
Molecular Medicine
Degree:
Master of Science
Document Type:
Master Thesis
Date of Defense:
April 13, 2015
Committee Members:
  • Dr Vandana Kalia, Thesis Advisor
Keywords:
  • CD8 T cell
  • Immunology
  • microRNA
  • Memory Differentiation
  • LCMV
  • Dicer.
Abstract:
During the last decade, post-transcriptional gene silencing by microRNAs (miRNAs) has been recognized as a major player in gene expression regulation and miRNAs have been found to be crucial for the effective orchestration of the adaptive immune response. In CD8 T cells, the absence of miRNAs mediated by deletion of the Ribonuclease III (RNAse III) enzyme Dicer in naïve cells has been shown to cause increased activation as well as defective accumulation, migration into the periphery, and effector cytokine production. However, these studies did not take into account the effects of defective activation on CD8 T cell differentiation and effector function that are unrelated to the absence of miRNAs. In our study, we used a novel mouse model in which only a subset of CD8 T cells in an otherwise WT environment lacks Dicer after optimal activation. For this, we used dicerfl/fl granzyme B-cre mice in which dicer is only deleted after successful activation and Granzyme B expression. Our study revealed that the diminished peak effector size of dicer-/- CD8 T cells is due to lack of sustained antigen-driven proliferation in the later stages of effector expansion and that lack of miRNAs only after optimal activation does not lead to defective migration or effector function as reported previously. Furthermore, we show that dicer-/- CD8 T cells exhibit increased contraction resulting in a severely diminished memory pool, even though the balance of terminal effector and memory CD8 T cells is skewed towards CD127Hi memory precursor effector cells (MPECs). Overall, our study reveals a critical role for miRNAs post-activation in driving terminal effector differentiation and the survival of CD8 T cells during the formation of an optimal memory pool.