Analysis of DOCK2 and SENP2 mutations on the immune system and CD8 T cell survival
type: CreativeWork
description: The discovery of genes essential for normal T cell numbers and T cell-mediated immune responses provides valuable insights into the adaptive immune system and targets for modulating disorders of immunity in cancer, transplantation, infection and autoimmunity. The studies presented in this thesis investigate two novel gene mutations that diminish the number of circulating T cells. The mutations were discovered by genome-wide ENU-mutagenesis in mice by flow cytometric screening of lymphocyte subsets in splenocytes and in peripheral blood. Genetic mapping and sequencing identified the two mutations. The first was a premature stop-gain mutation in Dock2, encoding a GTP exchange factor for the Rac family of cytoplasmic small G proteins, which has previously been found to be critical for T cells and immunity in mice and humans. The second mutation was a synonymous exonic nucleotide substitution in Senp2, encoding a specific protease for cleaving the ubiquitin-like SUMO protein from its conjugates with other proteins, whose critical role in T cells had not previously been shown. Mice homozygous for the ‘dockland’ E775X mutation in DOCK2 (doc/doc) had 80% fewer naïve (CD44low) CD8 and CD4 T cells, 70% fewer NKT cells, 50% fewer B cells in the blood and 80% fewer B cells in the spleen, and absence of splenic marginal zone B cells. Mutant T cells nevertheless divided normally to anti-CD3 in vitro, consistent with intact TCR signaling, and peripheral CD44high activated memory T cells were present in normal or increased numbers consistent with homeostatic proliferation. Thymocytes showed evidence of developmental defects, including 50% decreased CD4+CD8+ double positive (DP) cells with lower CD5 expression and greatly decreased NKT cells. The percentage of CD4+ or CD8+ single positive (SP) thymocytes lacking CD69 was increased, consistent with delayed egress of fully mature cells. In competitive bone marrow transplantation experiments, mutant hematopoietic stem cells engrafted …
abstract: The discovery of genes essential for normal T cell numbers and T cell-mediated immune responses provides valuable insights into the adaptive immune system and targets for modulating disorders of immunity in cancer, transplantation, infection and autoimmunity. The studies presented in this thesis investigate two novel gene mutations that diminish the number of circulating T cells. The mutations were discovered by genome-wide ENU-mutagenesis in mice by flow cytometric screening of lymphocyte subsets in splenocytes and in peripheral blood. Genetic mapping and sequencing identified the two mutations. The first was a premature stop-gain mutation in Dock2, encoding a GTP exchange factor for the Rac family of cytoplasmic small G proteins, which has previously been found to be critical for T cells and immunity in mice and humans. The second mutation was a synonymous exonic nucleotide substitution in Senp2, encoding a specific protease for cleaving the ubiquitin-like SUMO protein from its conjugates with other proteins, whose critical role in T cells had not previously been shown. Mice homozygous for the ‘dockland’ E775X mutation in DOCK2 (doc/doc) had 80% fewer naïve (CD44low) CD8 and CD4 T cells, 70% fewer NKT cells, 50% fewer B cells in the blood and 80% fewer B cells in the spleen, and absence of splenic marginal zone B cells. Mutant T cells nevertheless divided normally to anti-CD3 in vitro, consistent with intact TCR signaling, and peripheral CD44high activated memory T cells were present in normal or increased numbers consistent with homeostatic proliferation. Thymocytes showed evidence of developmental defects, including 50% decreased CD4+CD8+ double positive (DP) cells with lower CD5 expression and greatly decreased NKT cells. The percentage of CD4+ or CD8+ single positive (SP) thymocytes lacking CD69 was increased, consistent with delayed egress of fully mature cells. In competitive bone marrow transplantation experiments, mutant hematopoietic stem cells engrafted …
author: Mei, Yan (Angela)
language: en_AU
keywords: ENU, DOCK2, DOCK8, IL-7, SENP2
date published: 2018
date modified: 2026-07-24T00:55:04Z
provider: Australian National University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Australian National University

PropertyValue
property ID: Handle
value: http://hdl.handle.net/1885/165368