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Unique functional
properties of dendritic cells in HIV-1 elite controllers
Presented by Mathias Lichterfeld (United States).
J. Huang1, P. Burke1, F. Peyrera1, B. Walker1, L. Borges2, M. Lichterfeld3, X.G. Yu1
1Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Charlestown, United States, 2Amgen Inc., Seattle, United States, 3Infectious Disease Division, Massachusetts General Hospital, Boston, United States
Background: “Elite” controllers are HIV-1 infected
patients who maintain undetectable levels of HIV-1 viremia in the absence of
antiretroviral therapy. The Identification of unique immunological
characteristics in this specific patient population is a premier opportunity
for determining components of immune protection against HIV-1.
Methods: Antigen-presenting properties of
freshly isolated myeloid dendritic cells (mDC) were analyzed in mixed
lymphocyte reactions (MLR), followed by immunophenotypic characterization of
responding allogeneic T cells. Surface expression of leukocyte Immunoglobulin
like receptors (ILT) was analyzed by multiparameter flow cytometry. Secretion
of pro-inflammatory cytokines was detected using intracellular cytokine
staining. Targeted siRNA mediated gene knockout and specific blocking
antibodies were used to determine the specific functional effects mediated by
ILT receptors.
Results: In comparison to HIV-1
progressors or HIV-1 negative persons, mDC from “elite” controllers had
significantly (p< 0.001) better antigen-presenting properties, as determined
by MLRs. Moreover, elite
controllers preferentially induced memory-cell like allostimulatory responses
with upregulation of CD62L, CD127 and downregulation of CD57. In contrast, mDC
from elite controllers had weaker abilities to secrete pro-inflammatory
cytokines (TNF-a, IL-6 and IL-12p70) in comparison to HIV-1 progressors or
HIV-1 negative persons. This unique functional profile was associated with a
selective, highly significant (p< 0.01) phenotypic upregulation of the
immunoregulatory receptors ILT2 and ILT5 on mDC in elite controllers.
Inhibition of ILT2 or ILT5 with siRNA or blocking antibodies led to significant
reduction of the antigen-presenting properties of dendritic cells, consistent
with an immunostimulatory effect of these receptors on dendritic cell function.
Conclusions: HIV-1 “elite” controllers have myeloid dendritic cells with a unique
combination of increased antigen-presenting and decreased cytokine-section
properties. This extraordinary functional profile is mediated and maintained by
upregulation of the immunomodulatory receptors ILT2 and ILT5. Manipulation of
ILT-mediated dendritic cell function might thus represent a promising strategy
for immunological approaches to treatment and prevention of HIV-1 infection.
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