Generation and Regulation of Virus-specific Memory CD8 T Cells Público
Choo, Daniel Kwang Hyong (2010)
Abstract
Differentiation of CD8 T cells into cytotoxic T lymphocytes and subsequently into long-lived memory cells, which help provide protective immunity, is an important component of an effective adaptive immune response. This concept of "immunological memory" has resulted in the successful development of vaccines toward many human diseases. Despite this progress, there remain diseases (e.g. HIV and cancer) to which vaccines have yet to be successfully developed. Therefore, there is a continual need to better understand the requirements for the generation and maintenance of memory CD8 T cells. It is also crucial to further comprehend how these cells confer life-long protective immunity. We began by addressing the role of helper CD4 T cells in memory CD8 T cell development. Contrary to current dogma, we determined that CD4 T cell help was not required for either the "programming" or "maintenance" of memory cells. Instead, CD4 T cells were essential for the complete clearance of antigen and thereby, creating an ideal environment for memory development to occur. Next, we quantified the homeostatic turnover of memory CD8 T cells and addressed the role of helper CD4 T cells in the maintenance of the overall quality of memory cells. We found that all memory cells underwent turnover that was stochastic and independent of both CD4 T cell help and antigen-specificity. This turnover occurred at an average rate of 0.02 divisions/day (intermiotic time of ~50 days). Moreover, the overall quality (phenotypic profile and recall capability) was unaffected by the absence of CD4 T cell help during memory maintenance. Our final study focused on the migratory properties of CD8 T cells after LCMV infection. Utilizing FTY720 as a tool, we observed that the egress of effector cells from the peripheral lymph nodes, unlike their naïve predecessors, occurred independently of sphingosine-1-phosphate signaling. In addition, the pool of memory cells consisted of both tissue-resident and re-circulating cells that collectively worked to confer protective immunity. These studies should shed more light on the generation and regulation of "immunological memory" and hopefully will aid in the development of novel strategies toward diseases to which there are no current vaccines.
Table of Contents
Table of Contents
Table of Contents
List of Figures
List of Tables
Table of Contents
Chapter 1: Introduction...1
Tenets of CD8 T cell mediated immunological
protection...1
Different stages of CD8 T cell immune response...2
Expansion: generation of a protective CD8 T cell
immune response...3
Contraction: termination of CD8 T cell immune response...5
Activation-induced cell death...6
Activated T cell autonomous death...7
Maintenance: conferment of lifelong protective immunity...8
Different models of memory CD8 T cell differentiation...13
Divergent/Asymmetric model of memory
differentiation...13
Linear model of memory differentiation...15
Regulation of memory CD8 T cell differentiation...17
Duration and level of antigenic
stimulation...18
Inflammation...19
Precursor frequency...21
CD4 T cell help...23
Regulation of the homeostatic turnover and long-term maintenance of memory CD8 T cells...29
What are the rules that characterize the
homeostatic turnover of memory CD8 T cells?...30
Is the homeostatic turnover of memory CD8 T cells dependent on
epitope specificity?...31
What role do helper CD4 T cells play in the homeostatic turnover
and the long-term maintenance of memory CD8 T cells, in both their
quantity and their quality?...32
Utilizing the immunosuppressant drug FTY720 to study effector and memory CD8 T cell trafficking through different peripheral tissues...33
Naïve CD8 T cell trafficking into the
secondary lymphoid tissues...33
Egress of CD8 T cells from the peripheral lymph nodes...35
FTY720...36
Sphingosine-1-phosphate metabolism and its sources in
vivo...38
S1P receptor expression and the function of S1P on immune cell
trafficking...40
Mechanism of S1P/FTY720-mediated regulation of lymphocyte
trafficking through the peripheral LNs...42
"Programming" of memory CD8 T cell
trafficking...49
Resident vs Non-resident memory CD8 T cells...50
Chapter 2: Role of CD4 T cells in the development of fully functional LCMV-specific memory CD8 T cells...52
Abstract...52
Introduction...54
Results...57
Discussions...74
Materials and Methods...83
Figure Legends...85
Supplementary Figure Legends...92
Chapter 3: Dynamics of the homeostatic turnover and maintenance of LCMV-specific memory CD8 T cells...105
Abstract...105
Introduction...106
Results...108
Discussions...116
Materials and Methods...120
Figure Legends...123
Chapter 4: Utilizing the immunosuppressant drug FTY720 to study the migratory properties of virus-specific effector and memory CD8 T cells...132
Abstract...132
Introduction...134
Materials and Methods...139
Results/Discussions...141
Figure Legends...147
Chapter 5: Conclusions and Future Directions...155
References...161
List of Figures
Chapter 1: Introduction
1. Kinetics of CD8 T cell immune response during
an acute infection...3
2. Different models of IL-15 trans-presentation...10
3. Models of memory differentiation...13
4. Role of CD4 T cells in the activation of antigen-specific CD8 T
cells...24
5. Comparison of CD8 T cell immune response with and without CD4 T
cell help...27
6. Lymphocyte recirculation through a lymph node...36
7. Two models for the molecular mechanism of FTY720-induced
immunosuppression...46
Chapter 2: Role of CD4 T cells in the development of fully functional LCMVspecific memory CD8 T cells
1. Memory CD8 T cells generated in CD4 -/- mice
infected with acute LCMV are functionally and phenotypically
impaired...93
2. Absence of CD4 T cells during effector to memory transition, but
not during naïve to effector differentiation results in
impaired memory CD8 T cell development...94
3. Fully functional LCMV-specific memory CD8 T cells do develop in
the absence of TH cells...97
4. CD4 T cells are not required for the differentiation of all
LCMV-specific CD8 T cells into fully functional memory
cells...99
5. Absence of CD4 T cells during LCMV infection results in impaired
antigen clearance...101
6. Not the absence of CD4 T cells, but rather the persistence of
low level of LCMV antigen impedes normal memory CD8 T cell
development in LCMV-Armstrong infected CD4 -/- animals...102
7. Effector P14 CD8 T cells adoptively transferred into naïve
MHC class II -/- animals failed to develop into fully functional
memory CD8 T cells...103
Chapter 3: Dynamics of the homeostatic turnover and maintenance of LCMVspecific memory CD8 T cells
1. Longitudinal analysis of the long-term
maintenance of donor memory CD8 T cells...126
2. Quantitative analysis of the homeostatic turnover of donor
memory P14 CD8 T cells...127
3. Comparison of the homeostatic turnover of memory CD8 T cells
specific for different epitopes of LCMV...128
4. Analysis of the role of CD4 T cell help in both the long-term
maintenance and the homeostatic turnover memory CD8 T cells in WT
vs. CD4 -/- animals...129
5. Assessment of the role of CD4 T cell help in maintaining the
overall quality of fully functional memory CD8 T cells...131
Chapter 4: Utilizing an immunosuppressive drug FTY720 to study the migratory properties of virus-specific effector and memory CD8 T cells
1. Large number of LCMV-specific effector CD8 T
cells are observed in the peripheral tissues after infection in
FTY720 treated animals...149
2. The egress of LCMV-specific effector CD8 T cells from the LNs
can occur in the absence of sphingosine-1-phosphate
signaling...152
3. Overall pool of LCMV-specific memory CD8 T cells consists of
both re-circulating and tissue resident memory cells...154
List of Tables
Chapter 1: Introduction
1. S1P receptor expression and their effect on immune cells...40
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