Release of dendritic cells from cognate CD4⁺T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

Abstract

Resting dendritic cells (DCs) induce tolerance of peripheral T cells that have escaped thymic negative selection and thus contribute significantly to protection against autoimmunity. We recently showed that CD4 + Foxp3+ regulatory T cells (Tregs) are important for maintaining the steady-state phenotype of DCs and their tolerizing capacity in vivo. We now provide evidence that DC activation in the absence of Tregs is a direct consequence of missing DC-Treg interactions rather than being secondary to generalized autoimmunity in Treg-less mice. We show that DCs that lack MHC class II and thus cannot make cognate interactions with CD4 + T cells are completely unable to induce peripheral CD8 + T-cell tolerance. Consequently, mice in which interactions between DC and CD4 + T cells are not possible develop spontaneous and fatal cytotoxic T lymphocyte-mediated autoimmunity. DCs are bone marrow (BM)-derived, short-lived cells that play a key role in regulating immune responses. They are located at low frequency in lymphoid and nonlymphoid organs throughout the body, where they act as sentinels for invading pathogens. On recognition of pathogen-associated cues, DCs undergo a series of functional changes termed maturation, which is characterized by the up-regulation of costimulatory molecules such as CD80, CD86, and CD70, by the production of cytokines, such as IL-12, and by the expression of homing receptors, such as CCR7, that direct DC migration into the T-cell areas of secondary lymphoid organs. Together these changes allow DCs to efficiently activate naive T cells.Over the past decade, it has become clear that steady-state DCs play an important role in the maintenance of self-tolerance (1-3) and T-cell responsiveness (4). Because DCs can either prime or tolerize naive T cells, depending on their activation status, they are master regulators of adaptive immunity. How the maturation status of DCs translates into differential effects on naive T cells involves a variety of costimulatory and coinhibitory interactions between T cells and DCs. For example, we showed that tolerance induction depends on PD-1 and CTLA-4 (5), whereas blockade of CD70, a costimulatory molecule that is upregulated on activated DCs, prevents priming of CD8 + T cells even in the context of an infection (6). Along the same line, constitutive transgenic expression of CD70 on all DCs prevents the induction of tolerance and results in priming of a functional T-cell response by steady-state DCs (7).DC maturation can be triggered by numerous exogenous and endogenous stimuli that are usually associated with infection, inflammation, or damage (8 (10)(11)(12)(13)(14). Tregs may control self-reactive T-cell responses by direct interaction with conventional T cells or, alternatively, may act on DCs (15). Evidence for the latter comes from experiments in which depletion of Tregs results in Flt3-dependent increases in the number of DCs as well as in DC activation (9,11,16).When we combined the DIETER model of peripheral tolerance induction by steady-state DCs a...

The role of dendritic cells in autoimmunity

“…This genetic approach showed that steady-state antigen presentation by DCs induces a profound and irreversible unresponsiveness in CD8 + T cells; this includes the upregulation of the inhibitory molecules programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte antigen 4 (CTLA4) on CD8 + T cells 20 . The tolerogenic capacity of DCs in this context was enforced by MHC class II-dependent interactions with T Reg cells, and MHC class II-deficient DCs were proposed to induce CD8 + T cell-mediated autoimmunity 21 . Thus, DCs can induce peripheral T cell tolerance to immunodominant antigens that are expressed at high levels.…”

Molecular Control of Steady-State Dendritic Cell Maturation and Immune Homeostasis

“…MHC class II–impotency feedback does not exist in MARCH1-deficient B cells (although MARCH1-deficient B cells also overexpress MHC class II molecules) (211), pDCs (95), or FLT3-L-cultured BMDCs (217), indicating that unique in vivo requirements dictate MHC class II–impotency feedback on cDC functions. The mechanism of this feedback could involve cell-intrinsic or -extrinsic suppression of inappropriate MHC class II high DCs, perhaps transduced by MHC class II molecules (219, 220). cDCs of MARCH1-deficient mice may be analogous to hypothetical “exhausted” DCs (221–223) or to endotoxin tolerant macrophages, which are unresponsive to endotoxin stimulation partly as a result of altered NF-κB activation, chromatin modifications, and upregulated expression of negative regulators of signal transduction (179, 224, 225).…”

Dendritic Cell–MHC Class II and Itk Regulate Functional Development of Regulatory Innate Memory CD4+ T Cells in Bone Marrow Transplantation

“…Ablation of DCs in donor marrow leads to CD4 + T cell infiltration into multiple peripheral organs in syngeneic WT recipients (36), and bone marrow with DCs that are defective in cognate CD4 + T-cell recognition resulted in impaired peripheral tolerance, with fatal CD8 + T cell cytotoxicity in syngeneic WT recipients (37). Here we identified DCs as the primary hematopoietic cells expressing MHCII required for selection and/or “licensing” of functional IMP CD4 + T cells.…”