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We have previously shown that simultaneous engagement of the T cell receptor (TCR) and complement regulator CD46 on human CD4<jats:sup>+<\/jats:sup>T cells in the presence of interleukin-2 (IL-2) induces potent secretion of the immunomodulatory cytokine IL-10. These T cells mediate IL-10-dependent suppression of bystander CD4<jats:sup>+<\/jats:sup>T cells activated<jats:italic>in vitro<\/jats:italic>with anti-CD3 and anti-CD28 costimulation, reflecting a T regulatory type 1 (Tr1)-like phenotype. However, CD46-mediated negative regulation of pathogen-specific T cells has not been described. Therefore, we studied the ability of CD46-activated human CD4<jats:sup>+<\/jats:sup>T cells to suppress T cell responses to<jats:italic>Mycobacterium bovis<\/jats:italic>BCG, the live vaccine that provides infants protection against the major human pathogen<jats:italic>Mycobacterium tuberculosis<\/jats:italic>. Our results demonstrate that soluble factors secreted by CD46-activated human CD4<jats:sup>+<\/jats:sup>T cells suppress mycobacterium-specific CD4<jats:sup>+<\/jats:sup>, CD8<jats:sup>+<\/jats:sup>, and \u03b3<jats:sub>9<\/jats:sub>\u03b4<jats:sub>2<\/jats:sub>TCR<jats:sup>+<\/jats:sup>T cells. Dendritic cell functions were not downregulated in our experiments, indicating that CD46-triggered factors directly suppress pathogen-specific T cells. Interestingly, IL-10 appeared to play a less pronounced role in our system, especially in the suppression of \u03b3<jats:sub>9<\/jats:sub>\u03b4<jats:sub>2<\/jats:sub>TCR<jats:sup>+<\/jats:sup>T cells, suggesting the presence of additional undiscovered soluble immunoregulatory factors. Blocking endogenous CD46 signaling 3 days after mycobacterial infection enhanced BCG-specific T cell responses in a subset of volunteers. Taken together, these results indicate that CD46-dependent negative regulatory mechanisms can impair T cell responses vital for immune defense against mycobacteria. Therefore, modulating CD46-induced immune regulation could be integral to the development of improved tuberculosis therapeutics or vaccines.<\/jats:p>","DOI":"10.1128\/iai.00513-10","type":"journal-article","created":{"date-parts":[[2010,10,5]],"date-time":"2010-10-05T03:20:04Z","timestamp":1286248804000},"page":"5295-5306","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":19,"title":["CD46 Engagement on Human CD4<sup>+<\/sup>T Cells Produces T Regulatory Type 1-Like Regulation of Antimycobacterial T Cell Responses"],"prefix":"10.1128","volume":"78","author":[{"given":"Steven M.","family":"Truscott","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Immunobiology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Getahun","family":"Abate","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Immunobiology"},{"name":"St. Mary's Health Center, St. Louis, Missouri"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey D.","family":"Price","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Kemper","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John P.","family":"Atkinson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel F.","family":"Hoft","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Immunobiology"},{"name":"Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, Missouri"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.4.2544"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.12.6091"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI29251"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-07-2951"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1032"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1917"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.9.4385-4388.2004"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02696658"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.210391497"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1994.03510330076038"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.10.6711-6720.2005"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.283.19.2537"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.24.12013"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200939392"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.3.1722-1728.2001"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2004.09.002"},{"key":"e_1_3_2_18_2","first-page":"2840","volume":"104","year":"2004","unstructured":"Grossman, W. 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