| Abstract |
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease
characterized by synovial inflammation, which is orchestrated by both innate and
adaptive immune responses. Major hallmarks of autoimmunity in this disease include
the appearance of serum autoantibodies and the persistent activation of self-reactive
CD4+ cells. Although therapeutic strategies targeting cytokines and B or T cells have
had a major clinical impact, disease in many patients remains refractory to current
biologic interventions, and for patients who show a response to therapy, true
remission associated with reestablishment of immune tolerance is rare. This has
increased the interest in exploring strategies to reestablish immune tolerance and
provide longterm disease suppression.
Dendritic cells (DCs) are professional antigenpresenting cells (APCs) that can induce
either immunity or tolerance. Myeloid DCs and plasmacytoid DCs represent the 2
major subsets of DCs, with human plasmacytoid DCs defined as
CD45+CD123+CD303+CD11c- cells and myeloid DCs defined as
CD45+CD1a+CD11c+CD1c+ cells. Although both subsets exhibit a functional
plasticity in directing T cell responses, current evidence supports a predominant role
of plasmacytoid DCs in the maintenance of tolerance through the expansion/induction
of Treg cells. To date, two major subsets of Treg cells have been described: thymusderived
Foxp3+ Treg cells and adaptive interleukin-10 (IL-10)–producing Treg cells
(Tr1 cells) generated in the peripheral blood.
The importance of Treg cells in the maintenance of tolerance is highlighted by the
development of spontaneous multiorgan autoimmunity following Treg cell deletion in
rodents. In humans, reduced numbers of Treg cells and impaired function of Treg
cells have been reported in patients with autoimmune diseases such as rheumatoid
arthritis (RA), systemic lupus erythematosus, and multiple sclerosis. The molecular
pathways involved in prompting plasmacytoid DCs to promote Treg cell development
are not fully understood. Expression of the indoleamine 2,3-dioxygenase (IDO)
enzyme by plasmacytoid DCs is thought to play a significant role in plasmacytoid
DC–mediated Treg cell induction.
Whether human DCs exploit similar mechanisms of Treg cell induction that might
facilitate reestablishment of tolerance in a disease setting remains to be seen.
Cytokine-directed therapy may have an impact on Treg cell function. Thus, Treg cells
in patients with active RA are functionally defective. Anti–tumor necrosis factor α
8
(anti-TNFα) therapy reverses this defect, through conversion of naive T cells into
Foxp3+ Treg cells. Whether therapy may also have an impact on DCs, in terms of
changing their effects on Treg cells, has not been explored.
Herein, we present findings demonstrating that plasmacytoid DCs isolated from
patients with RA whose disease is in remission induce an additional, distinct
population of Treg cells, Tr1 regulatory cells, in a manner that is dependent on the
presence of IDO. Unlike the previously described anti-TNFα–induced Treg cells, this
population of genuine Tr1 cells does not express Foxp3 but, instead, secretes high
levels of IL-10. Most notably, these cells suppress the proliferation of autologous
naive CD4+ cells, in a dose-dependent manner.
Finally, we studied how IL-21 cytokine effects on the function of pDCs, given that
IL-21 is found in high levels at the periphery of autoimmune diseases such as
systemic erythematosus lups (SLE). IL-21 is an immunomodulatory cytokine that is
implicated in the pathogenesis of autoimmune diseases, by promoting B cells
differentiation, or by affecting Th17 and Tregs function. Dendritic cells are potential
regulators of immune responses, since mature dendritic cells promote autoimmunity,
while immature dendritic cells promote tolerance. Thus, we studied the potential of
dendritic cells matured in the presence of IL-21 to affect on the activation and
proliferation of naïve T cells.
Our results suggest that dendritic cells matured in the presence of IL-21 significantly
promote the proliferation of allogeneic CD4+CD25- T cells, when IL-21 is present
during the activation of T cells. This increased proliferation correlates well with high
levels of IFN-γ and TNF-α. Together our results highlight the intrinsic ability of pDCs
to regulate T cell responses in an autoimmune setting in humans and further support
the use of pDCs as a potential therapeutic modality for autoimmune diseases and
transplantation.
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