Over the past decade it has become accepted that some T
cells play a role in dampening down immune responses. These cells are dubbed
regulatory T cells or Treg for short. In lab studies, Treg have been shown to
suppress the activation of other T cells, and there is considerable evidence
that this regulatory function is also performed in vivo. One problem, however,
is that there are no definitive markers for Tregs. Initially,
expression of a molecule called CD25 was used to define Treg, but CD25 can also
be upregulated by other activated T cells. More recently, a transcription
factor, Foxp3, has emerged as a more specific marker for Treg. Although
several studies have explored the role of Treg in HIV infection, results have
been inconsistent and hard to interpret because approaches to define the cells
have varied. A new study in the journal AIDS Research & Human Retroviruses uses
the combination of CD25 and Foxp3 to explore whether Treg levels differ in
individuals with varying rates of disease progression.
Weiwei Cao and colleagues from UCLA employed a case-control
approach to compare twenty fast progressors from the Multicenter AIDS Cohort
Study (MACS) to forty matched slow progressors and nine uninfected individuals.
Fast progression was defined as an AIDS diagnosis within 4 years after
enrollment into MACS, whereas slow progressors were categorized based on the
absence for an AIDS diagnosis for at least 8 years after entry into the cohort.
Treg constituted 4.6% of CD4 T cells in uninfected study participants and this
proportion was only slightly increased to 5.6% in slow progressors. Among fast
progressors, however, the proportion of Treg was significantly higher at
11.3%. Further analysis showed
that Treg levels correlated with CD4 T cell activation; the proportion of CD4 T
cells expressing the activation marker CD38 was 1.5% in uninfected individuals,
7.2% in slow progressors and 16.3% in fast progressors.
In the discussion section of the paper, Cao and colleagues suggest
that these two phenomena may be linked, because other studies have shown that T
cell activation can lead to the generation of Foxp3-expressing Treg from
resting T cells that previously did not express the marker. Therefore it is
possible that the persistently elevated levels of T cell activation in HIV
infection leads to the observed accumulation of Tregs. Some researchers have
suggested that immune activation in HIV infection is caused by a lack of Treg,
but Cao and colleagues note that their data appears incompatible with this
possibility. Rather, their data argues that Treg either have a negative effect
– perhaps by interfering with HIV-specific immune responses, as some prior
studies have posited – or alternatively the relative expansion of Tregs is just
a by-product of immune activation which has no specific role in HIV disease
progression.
AIDS Research and Human Retroviruses. February 2009, 25(2):
183-191. doi:10.1089/aid.2008.0140.
Regulatory T Cell Expansion and Immune Activation during
Untreated HIV Type 1 Infection Are Associated with Disease Progression (free access to full text PDF)
Weiwei Cao,1 Beth D. Jamieson,2 Lance E. Hultin,1 Patricia
M. Hultin,1 and Roger Detels1
1Department of Epidemiology, School of Public Health,
University of California, Los Angeles, California 90095.
2Department of Medicine, Division of Hematology and
Oncology, David Geffen School of Medicine, University of California, Los
Angeles, California 90095.
Abstract
Regulatory T cells (Tregs) may play an important role in the
immunopathology of chronic HIV-1 infection due to their potent suppressive
activity of both T cell activation and effector function. To investigate the
correlation between Tregs and immune activation during untreated chronic HIV-1
infection, we conducted a nested case–control study within the Multicenter AIDS
Cohort Study (MACS). Twenty HIV-1-infected fast progressors (FP) and 40 slow
progressors (SP) were included in our study using risk-set sampling. Nine
age-matched HIV-1-uninfected men (UI) were also included. Cryopreserved
peripheral blood mononuclear cells (PMBCs) were tested using flow cytometry
analyses. We identified Tregs as Foxp3+CD25+CD4+ T cells and assessed the
activation of CD4+ and CD8+ T cells by the expression of CD38, HLADR, or both
markers simultaneously. There is a relative expansion of Tregs during HIV-1
infection, which is associated with disease progression. The increased CD38
expression on both CD4+ and CD8+ T cells expressed as either percentage or
median fluorescence intensity (MFI) and the elevated proportion of CD8+ T cells
that is HLADR+CD38+ were all associated with rapid HIV-1 progression. Counter
to the assumed role of Tregs as the suppressors of activation, the expansion of
Tregs was positively correlated with CD4+ T cell activation among
HIV-1-infected fast progressors. The high level of Tregs associated with rapid
HIV progression may suggest a detrimental role of these cells in the immune
control of HIV-1 infection.
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