{"doi":"10.3389/fimmu.2021.710406","title":"Macrophage-Regulatory T Cell Interactions Promote Type 2 Immune Homeostasis Through Resistin-Like Molecule α","abstract":"RELMα is a small, secreted protein expressed by type 2 cytokine-activated “M2” macrophages in helminth infection and allergy. At steady state and in response to type 2 cytokines, RELMα is highly expressed by peritoneal macrophages, however, its function in the serosal cavity is unclear. In this study, we generated RELMα TdTomato (Td) reporter/knockout (Rα Td ) mice and investigated RELMα function in IL-4 complex (IL-4c)-induced peritoneal inflammation. We first validated the RELMα Td/Td transgenic mice and showed that IL-4c injection led to the significant expansion of large peritoneal macrophages that expressed Td but not RELMα protein, while RELMα +/+ mice expressed RELMα and not Td. Functionally, RELMα Td/Td mice had increased IL-4 induced peritoneal macrophage responses and splenomegaly compared to RELMα +/+ mice. Gene expression analysis indicated that RELMα Td/Td peritoneal macrophages were more proliferative and activated than RELMα +/+ macrophages, with increased genes associated with T cell responses, growth factor and cytokine signaling, but decreased genes associated with differentiation and maintenance of myeloid cells. We tested the hypothesis that Rα Td/Td macrophages drive aberrant T cell activation using peritoneal macrophage and T cell co-culture. There were no differences in CD4 + T cell effector responses when co-cultured with RELMα +/+ or RELMα Td/Td macrophages, however, RELMα Td/Td macrophages were impaired in their ability to sustain proliferation of FoxP3 + regulatory T cells (Treg). Supportive of the in vitro results, immunofluorescent staining of the spleens revealed significantly decreased FoxP3 + cells in the RELMα Td/Td spleens compared to RELMα +/+ spleens. Taken together, these studies identify a new RELMα regulatory pathway whereby RELMα-expressing macrophages directly sustain Treg proliferation to limit type 2 inflammatory responses.","journal":"Frontiers in Immunology","year":2021,"id":171830,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9528,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":706797,"name":"Sang Yong Kim","orcid":"0000-0001-5571-1393","position":1,"is_corresponding":false},{"id":689793,"name":"Nancy M. Lainez","orcid":"0000-0002-3191-9023","position":2,"is_corresponding":false},{"id":689794,"name":"Djurdjica Coss","orcid":"0000-0003-0692-1612","position":3,"is_corresponding":false},{"id":260349,"name":"Meera G. Nair","orcid":"0000-0002-1807-5161","position":4,"is_corresponding":false},{"id":706796,"name":"Jiang Li","orcid":"0000-0001-5596-9159","position":0,"is_corresponding":true}],"reference_count":84,"raw_metadata":null,"created_at":"2026-07-18T23:46:33.067299Z","pmid":"34349768","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}