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.
Highlights
Dendritic cells (DCs) play roles in pathogen defense and for maintaining tolerance to self-antigens [1,2,3]
We could show in RelB+/− mice that steady-state migratory DCs (ssmDCs) of skindraining Peripheral LN (PLN) expressed the highest levels of RelB under steadystate conditions [15]
Further analyses of PLN DC indicated that the CD11c+ CD40high ssmDCs but not the CD11c+ CD40low resident DCs were increased in RelBDCko mice (Figures 1A,B), while the total lymph node and spleen cell numbers remained unchanged (Figure S3 in Supplementary Material)
Summary
Dendritic cells (DCs) play roles in pathogen defense and for maintaining tolerance to self-antigens [1,2,3]. DC migration in the steady state is accompanied by a partial maturation process (semimature) that is distinct from pathogen-matured DC by the lack of pro-inflammatory cytokine production [9]. This concept has recently been confirmed by transcriptional profiling [10]. SsmDCs can pick up soluble peptide antigens delivered by osmotic minipumps and the subsequent antigen presentation in the lymph nodes results in de novo conversion of naive T cells into induced Foxp3+ Tregs (iTregs) [12, 13]. The functional importance of Treg induction by ssmDCs has been shown by their role in the protection from autoimmunity [8]
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