Control of the homeostatic regulatory T cell pool by RelB expression in steady state migratory dendritic cells

• Applicant: Professor Dr. Manfred Lutz
• Subject Area: Immunology
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 233384519

Interactions of dendritic cells (DCs) with regulatory T cells (Tregs) play a key role for immune tolerance by controlling Treg induction, maintenance and proliferation. Using a transgenic mouse expressing ovalbumin (OVA) as a neo-self-antigen under the keratin-5 promoter in the epidermis (K5-mOVA) and OVA-specific CD4+ T cell receptor transgenic mice (OT-II), we found previously that OVA-self-antigen presentation in the draining lymph nodes strictly depends on the transport by steady state migratory DCs (ssmDCs) and leads to conversion of naive CD4+ T cells into CD4+ Foxp3+ Tregs. Using mice with genetic deficiencies for the NF-kB/Rel transcription factor family members RelB, p52 or p50 we could show that the alternative NF-kB signaling pathway through RelB/p52 controls the migration of ssmDCs and thereby Tregs.To gain deeper insights into the specific role of the RelB transcription factor for ssmDCs, Tregs and peripheral tolerance, we started now to investigate mice that specifically lack RelB in CD11c+ DCs (RelBDCko). This could achieved by crossing Cre recombinase expressing mice under the DC-specific promoter CD11c (CD11c-Cre) with mice where both RelB alleles are flanked by loxP sites (RelBfl/fl). Our preliminary data indicate that RelBDCko mice appear largely normal. However, they show increased frequencies of ssmDCs in peripheral lymph nodes, of CD4+ Foxp3+ Tregs and of an IL-2-producing (presumably IL-7-dependent) CD4+ CD44high T cell subset in thymus, lymph nodes and spleen. In this proposal we would like to study the functional relations between these three cell types. We hypothesize that in the absence of RelB in ssmDCs the binding partner p52 forms alternative conjugates with other NF-kB/Rel family members that we will identify. Then we want to test whether the IL-2 or IL-7 release is altered in DC or T cells of RelBDCko mice and how RelB-deficiency influences the ssmDC turnover. By using the K5-mOVA/OT-II system we want to study the impact of RelB-deficiency by DCs on natural and inducible Treg subsets and whether it requires antigen-specificity. We will ask which surface receptors or the IL-2/IL-7 cytokines contribute to the increased steady state frequencies of Treg and CD4+ CD44high T cells in RelBDCko mice. Finally we want to determine if the tolerance threshold of RelBDCko mice with elevated levels of Tregs is increased after induction of allergy or autoimmunity.Together this project will contribute to answer the question how steady state levels of Tregs are adjusted in vivo and how these manipulations of Treg populations influence susceptibility against allergy or autoimmunity.

• DFG Programme: Research Grants