RelB+ Steady-State Migratory Dendritic Cells Control the Peripheral Pool of the Natural Foxp3+ Regulatory T Cells

Abstract

Thymus-derived natural Foxp3+ CD4+ regulatory T cells (nTregs) play a key role in maintaining immune tolerance and preventing autoimmune disease. Several studies indicate that dendritic cells (DCs) are critically involved in the maintenance and proliferation of nTregs. However, the mechanisms how DCs manage to keep the peripheral pool at constant levels remain poorly understood. Here, we describe that the NF-κB/Rel family transcription factor RelB controls the frequencies of steady-state migratory DCs (ssmDCs) in peripheral lymph nodes and their numbers control peripheral nTreg homeostasis. DC-specific RelB depletion was investigated in CD11c-Cre × RelBfl/fl mice (RelBDCko), which showed normal frequencies of resident DCs in lymph nodes and spleen while the subsets of CD103− Langerin− dermal DCs (dDCs) and Langerhans cells but not CD103+ Langerin+ dDC of the ssmDCs in skin-draining lymph nodes were increased. Enhanced frequencies and proliferation rates were also observed for nTregs and a small population of CD4+ CD44high CD25low memory-like T cells (Tml). Interestingly, only the Tml but not DCs showed an increase in IL-2-producing capacity in lymph nodes of RelBDCko mice. Blocking of IL-2 in vivo reduced the frequency of nTregs but increased the Tml frequencies, followed by a recovery of nTregs. Taken together, by employing RelBDCko mice with increased frequencies of ssmDCs our data indicate a critical role for specific ssmDC subsets for the peripheral nTreg and IL-2+ Tml frequencies during homeostasis.

RelB Deficiency in Dendritic Cells Protects from Autoimmune Inflammation Due to Spontaneous Accumulation of Tissue T Regulatory Cells

“…This may indicate that IL-33 expands Tregs to prevent tissue damage (e.g., during ongoing type 2 immune-driven inflammation) but is not the primary driver for the tissue Treg phenotype under physiologic conditions. Alternatively, IL-2/anti-IL-2 Ab complexes are able to induce high numbers of Gata3-expressing Tregs, and activation of T cells by RelBdeficient DCs has been shown to result in increased IL-2 production by T cells or DCs (6,63,65), but we did not find any difference in systemic IL-2 or IL-33 cytokine levels in the serum or peritoneal lavage of RelB DDC mice.…”

Tolerogenic Transcriptional Signatures of Steady-State and Pathogen-Induced Dendritic Cells

“…The individual roles and mechanisms of tolerogenicity are explained below or referred to in Tables 1 – 5 . Although the extent to which GM-CSF-derived BM-DCs resemble cDCs is still a matter for debate ( 18 ), the tolerogenic signatures observed in spontaneously matured BM-DCs ( 19 ) are strikingly similar to those observed in ssmDCs ( 14 – 16 ) (Table 1 ).…”

“…To identify tolerogenic DC signatures after pathogen stimulation, we first sought to identify comparative DC subsets known for their tolerogenic function as a reference dataset. While CCR7 − resident DCs appear at an immature stage, CCR7 + ssmDCs undergo a homeostatic maturation process reaching a semi-mature stage, which is characterized by low expression of MHC II and costimulatory molecules, such as CD40 and CD86, and the absence of proinflammatory cytokine production ( 13 – 16 ). In several respects, steady-state plasmacytoid DCs (pDCs) resemble resident CD4 + or CD8α + conventional DCs (cDCs) of cutaneous lymph nodes and spleen (Figure 1 ).…”

“…After pathogen-induced maturation DCs upregulate MHC II, CD40 and CD86 molecules on their surface ( 14 , 15 ). Depending on the stimulus, mature RelB +++ , RelA +++ , and cRel +++ DCs differ qualitatively in the production of the proinflammatory cytokines IL-6, TNF, IL-1β, IL-12p70, IL-23, or type-I interferon, while RelB +++ , RelA + , and cRel + ssmDCs induce Tregs by their release active TGF-β + from its latent form of surface-bound latency-associated peptide (LAP) molecules ( 14 – 16 ). While tolerogenic functions of ssmDCs have been described by many authors, the demonstration of T cell tolerogenicity by immature lymph node-resident DCs is much less understood ( 17 ).…”

Biological characteristics of transcription factor RelB in different immune cell types: implications for the treatment of multiple sclerosis

“…Moreover, the activation of the noncanonical NF-κB pathway via RelB/p52 is essential for maintaining the frequency of steady-state migratory DCs and inducing Foxp3+ iTreg formation by steady state migratory RelB+ Langerin+ dermal DCs [165]. RelB+ Langerin− dermal DC subset controls the peripheral pool of Foxp3+ nTregs [166]. Further, some researchers found Foxp3+ Tregs markedly expanded in mice with RelB depletion because of increased levels of IL-2, a growth factor for Foxp3+ Tregs that is produced by hyperactive T effector cells [167].…”