Many years ago a
study in mice suggested that maintenance of normal T cell numbers was “blind”
to whether the T cells belonged to the CD4 or CD8 lineage. This led some
researchers to propose that the increase in CD8 T cell counts seen in HIV-positive
people reflected an effort by the immune system to maintain overall T cell
numbers in response to the loss of CD4 cells. The technical term used to
describe this theory was “blind homeostasis.” However, it wasn’t long before
additional research in mice revealed that maintenance of CD4 and CD8 T cell
numbers involves lineage-specific factors such as signaling via MHC class II
molecules in the case of CD4 cells and MHC class I molecules for CD8 cells.
Studies also began to delineate the primary role of persistent immune
activation in HIV pathogenesis, and it became evident that differences in how
CD4 and CD8 cells respond to persistent activation likely underlies the skewing
of the CD4:CD8 ratio that occurs both in HIV-positive people and the very
elderly. A few holdouts have continued to reference the blind homeostasis
theory, even very recently, but now
a careful study conducted in sooty mangabeys and rhesus macaques completely
lays the idea to rest.
The researchers, headed by Mirko Paiardini at the University
of Pennsylvania, used monoclonal antibodies to deplete either CD4 or CD8 T
cells in the two monkey species and then monitored the response to the
depletion. Contrary to the blind homeostasis theory, CD8 T cells were not
significantly affected by CD4 depletion and vice versa. As has been seen in
humans after transplant-related or HIV-induced depletion of T cells,
reconstitution of CD4 T cells was slower and less complete than for CD8 T cells
(out to 180 days of follow up). The researchers also looked for differences
between sooty mangabeys and rhesus macaques because SIV is largely
non-pathogenic in the former species but causes simian AIDS in the latter, and
one suggested explanation for this difference is that sooty mangabeys may replenish
lost CD4 T cells faster. Overall, no significant differences were found, but
when the speed of reconstitution was compared for naïve and memory subsets of
CD4 cells it emerged that naïve cell numbers increased somewhat more rapidly in
sooty mangabeys (additional research will be required to address the question
of whether this difference is connected to the relative resistance of sooty
mangabeys to AIDS). The researchers note that, up until now, there have been
few studies addressing how T cell homeostasis is normally maintained in
non-human primates and this is an obstacle to understanding mechanisms of T
cell depletion and repletion in humans.
A separate paper in the Journal of Immunology looks at the
effects of aging on T cell homeostasis and the response to vaccination in rhesus
macaques. As happens in humans, naïve CD4 and CD8 T cell numbers decline as
these animals age, and the memory T cell pool becomes increasingly dominated by
cells targeting certain antigens (these are called oligoclonal T cell
expansions). The researchers show that the extent of these changes predicted
the magnitude of the immune response to a new vaccine (modified vaccinia Ankara
strain or MVA) in the old macaques in their study. It has been suggested that
changes in the function of antigen-presenting dendritic cells (DC) may also
contribute to poor responses to vaccines in the elderly, but in this study no
discernible defects in DC function were detected when old and young animals
were compared. The results suggest that speeding naïve T cell reconstitution is
an important target for immunotherapy, particularly in HIV infection where
naïve CD4 and CD8 T cells are eroded at an accelerated rate compared to normal
aging.
Blood First Edition Paper, prepublished online May 18, 2010;
DOI 10.1182/blood-2010-01-263814.
Submitted January 25, 2010; accepted April 23, 2010.
Jessica C. Engram1, Barbara Cervasi1, Jose A.M. Borghans2,
Nichole R. Klatt3, Shari N. Gordon4, Ann Chahroudi1, James Else5, Robert S.
Mittler5, Donald L. Sodora6, Rob J. de Boer7, Jason M. Brenchley3, Guido
Silvestri1 and Mirko Paiardini1,*
1 Department of Pathology, University of Pennsylvania,
Philadelphia, United States; 2 Department of Immunology, Utrecht Medical
Center, Utrecht, Netherlands; 3 Viral Pathogenesis and Vaccine Section,
Laboratory of Molecular Microbiology, National Institutes of Health, Bethesda,
Maryland, United States; 4 Animal Models and Retroviral Vaccine Section,
National Cancer Institute, National Institutes of Health, Bethesda, Maryland,
United States; 5 Yerkes National Primate Research Center, Emory University,
Atlanta, United States; 6 Seattle Biomedical Research Institute, Seattle,
Washington, United States; 7 Theoretical Biology, Utrecht University, Utrecht,
Netherlands
Many features of T-cell homeostasis in primates are still
unclear, thus limiting our understanding of AIDS pathogenesis, in which T-cell
homeostasis is lost. Here, we performed experiments of in vivo CD4+ or CD8+
lymphocyte depletion in two non-human primate species, i.e. rhesus macaques
(RMs) and sooty mangabeys (SMs). While RMs develop AIDS following infection
with simian immunodeficiency virus (SIV), SIV-infected SMs are typically
AIDS-resistant. We found that, in both species, most CD4+ or CD8+ T-cells in
blood and lymph nodes were depleted following treatment with their respective
antibodies. These CD4+ and CD8+ lymphocyte depletions were followed by a
largely lineage-specific CD4+ and CD8+ T-cell proliferation, involving mainly memory
T-cells, which correlated with interleukin-7 plasma levels. Interestingly, SMs
showed a faster repopulation of naïve CD4+ T-cells than RMs. In addition, in
both species CD8+ T-cell repopulation was faster than that of CD4+ T-cells,
with CD8+ T-cells reconstituting a normal pool within <60 days and CD4+
T-cells remaining below baseline levels up to day 180 post-depletion. While
this study revealed subtle differences in CD4+ T-cell repopulation in an
AIDS-sensitive versus an AIDS-resistant species, such differences may have
particular relevance in the presence of active SIV replication, where CD4+
T-cell destruction is chronic.
Published online May 17, 2010
The Journal of Immunology, 2010,
doi:10.4049/jimmunol.0904193
Luka Cicin-Sain, Sue Smyk-Paerson, Noreen Currier, Laura
Byrd, Caroline Koudelka, Tammie Robinson, Gwendolyn Swarbrick,Shane Tackitt,
Alfred Legasse, Miranda Fischer, Dragana Nikolich-Zugich, Byung Park, Theodore
Hobbs, Cynthia J. Doane, Motomi Mori, Michael T. Axthelm, Deborah A. Lewinsohn,
and Janko Nikolich-Zugich
Vaccine and Gene Therapy Institute and Oregon National Primate Research
Center, Oregon Health and Science University, Beaverton, OR 97006; Department
of Pediatrics, Department of Public Health and Preventive Medicine, and Oregon Clinical and Translational
Research Institute, Oregon Health and Science University, Portland, OR 97239;
and Department of Immunobiology and the Arizona Center on Aging, University of
Arizona College of Medicine, Tucson, AZ 85719
Aging is usually accompanied by diminished immune protection
upon infection or vaccination. Although aging results in well-characterized
changes in the T cell compartment of long-lived, outbred, and pathogen-exposed
organisms, their relevance for primary Ag responses remain unclear. Therefore,
it remains unclear whether and to what extent the loss of naive T cells, their
partial replacement by oligoclonal memory populations, and the consequent
constriction of TCR repertoire limit the Ag responses in aging primates. We
show in this study that aging rhesus monkeys (Macaca mulatta) exhibit poor CD8
T cell and B cell responses in the blood and poor CD8 responses in the lungs
upon vaccination with the modified vaccinia strain Ankara. The function of APCs
appeared to be maintained in aging monkeys, suggesting that the poor response
was likely intrinsic to lymphocytes. We found that the loss of naive CD4 and
CD8 T cells, and the appearance of persisting T cell clonal expansions
predicted poor CD8 responses in individual monkeys. There was strong
correlation between early CD8 responses in the transitory CD28+ CD62L– CD8+ T
cell compartment and the peak Ab titers upon boost in individual animals, as
well as a correlation of both parameters of immune response to the frequency of
naive CD8+ T cells in old but not in adult monkeys. Therefore, our results
argue that T cell repertoire constriction and naive cell loss have prognostic
value for global immune function in aging primates.
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