|
What’s New in Immunology? Mechanisms of T Cell Dysfunction |
TUSY4 |
|
| Type: |
|
| Venue: |
Parkside Ballroom B |
|
|
| Time: |
16:30 - 18:00, Tuesday, 24.07.2007 |
| Code: |
TUSY4 |
|
Co-Chairs: |
Barbara Fazekas de St. Groth, Australia
Bruce D. Walker, United States
|
|
|
This session will summarize recent data that explains reasons why the adaptive immune system fails to control HIV infection. The session will review animal models and clinical studies that have identified novel mechanisms of T cell exhaustion including the role of PD-1 and its ligands, T regulatory cells and suppression of antiviral cytokines. Potential therapeutic strategies that may overcome T cell exhaustion will also be presented.
|
|
Presentations in this session:16:30
TUSY401 | Introduction and overview
Bruce D. Walker, United States
| 16:40
TUSY402
Powerpoint (2.24 MB) | Bacterial translocation and T cell dysfunction in HIV
Jason Brenchley, United States
| 17:00
TUSY403 | T cell exhaustion in HIV infection: can it be reversed?
Rafick Sekaly, Canada
| 17:20
TUSY404
Powerpoint (3.14 MB) | Resolution of acute immune activation: A major determinant of SIV disease outcome
Jake Estes, United States
| 17:40
TUSY405 | T cell dynamics in IL-7 treated Rhesus macaques, application to the clinic
Remi Cheynier, France
|
|
Audio files:-
 audio file - high quality (mp3 format, 41.9 MB) - audio file - low quality (mp3 format, 21.1 MB)
|
Rapporteur report
Track A: HIV Basic Science report by John Zaunders
Bruce Walker highlighted our need to better understand why some CD8
responses are much more effective than others. This may be at the level
of antigen processing of particular epitopes, which is by-passed in
most in vitro assays. Assays of inhibition of viral replication may
better reflect in vivo efficacy. Up-regulation of PD-1 on CD8
cells may be involved in limiting effectiveness of HIV-specific CTL
responses. It has now also been found that HIV-specific CD4+ T cells
over-express PD-1 and CTLA-4 ex vivo, particularly in subjects with
progressive disease. In contrast, LTNP have less expression of PD-1 and
CTLA-4, and elite controllers have the least expression.
About 40% of elite controllers have no identified host genetic traits
associated with viral control, and genome wide association studies are
underway. Around 300 elite controllers have supplied samples (out of a
projected 1000) through their primary physicians, world-wide.
Jason Brenchley described his results on translocation of microbial
products, from the lumen of the gastrointestinal tract to plasma,
through a leaky mucosal epithelium, resulting from the dramatic
depletion of CD4+ T cells during primary HIV infection. Initially, this
microbial translocation was measured as the concentration of LPS in
plasma, but has now been extended to peptidoglycan and bacterial 16S
DNA. The plasma level of LPS was correlated with clinical outcome, with
the highest level in progressive disease with lower levels in LTNP, and
also correlated with immune activation of T cells, and reduced CD4 cell
counts.
Raficke Sekaly reported his studies on T cell exhaustion and T cell
survival. Central memory T cells are self-renewing long-term surviving
cells dependent on gamma chain cytokines. The studies identified a
transcription factor FOXO3a as central to regulation of survival.
Phosphorylated FOXO3a is retained in the cytoplasm, but
unphosphorylated FOXO3a enters the nucleus and initiates transcription
of pro-apoptotic genes, notably Bim and P130. Phosphorylation is driven
by IL-2 or IL-7, combined with TCR/CD28 signalling, and mediated by IKK
and AKT, but reversed by DUSP-6. Central memory cells from HIV+ LTNP
exhibit decreased apoptosis and increased survival, compared with
progressive disease. These differences in LTNP were associated with
increased phosphorylated FOXO3a. An N-terminal mutant FOXO3a blocked
endogenous FOXO3a in T cells from progressive HIV infection, and led to
increased cell survival in vitro.
Jake Estes reported studies on T cell activation and the T regulatory
cell pathway comparing pathogenic primary SIV infection of rhesus
macaques and non-pathogenic primary infection of sooty mangabeys. The
levels of immune activation were similar in both models very early in
infection, but resolved only in sooty mangabeys. This resolution was
associated with early up-regulation of PD-1 (a marker of “exhausted”
CD8 T cells in chronic viral infections), and lower up-regulation of
granzyme B. In contrast, in rhesus macaques there was much higher
up-regulation of granzyme B, and no appearance of PD-1 until the
chronically activated, heavily CD4-depleted, lymph node disrupted phase
in these animals. This represents a major T cell regulatory difference
associated with the different pathological outcomes.
Remi Cheynier reported the effect of recombinant IL-7 on T cell subsets
in rhesus macaques. Injection of IL-7 led to a transient decrease in
CD4 and CD8 cells, but this was followed by a durable increase in these
cells. The transient decline was not due to apoptosis, but was
associated with upregulation of CXCR4 and CCR9, and greatly increased
numbers of cells in ileum and jejunum. There was transient
proliferation of cells in the first week, especially within the thymus,
and increase of Bcl-2 expression for at least 30 days. Together, this
led to accumulation and survival of peripheral cells.
In a human trial of IL-7 treatment in HIV-infected subjects on HAART,
recombinant glycosylated h-IL-7 led to large increases in CD4 and CD8
cell counts, peaking at day 21, but remaining higher at wk 52. There
was no increase in viral load, and a good safety profile.
|
|
|