Immune Surveillance by Natural IgM Is Required for Early Neoantigen Recognition and Initiation of Adaptive Immunity

Am J Respir Cell Mol Biol. 2018 Nov;59(5):580-591. doi: 10.1165/rcmb.2018-0159OC.


Early recognition of neoantigen-expressing cells is complex, involving multiple immune cell types. In this study, in vivo, we examined how antigen-presenting cell subtypes coordinate and induce an immunological response against neoantigen-expressing cells, particularly in the absence of a pathogen-associated molecular pattern, which is normally required to license antigen-presenting cells to present foreign or self-antigens as immunogens. Using two reductionist models of neoantigen-expressing cells and two cancer models, we demonstrated that natural IgM is essential for the recognition and initiation of adaptive immunity against neoantigen-expressing cells. Natural IgM antibodies form a cellular immune complex with the neoantigen-expressing cells. This immune complex licenses surveying monocytes to present neoantigens as immunogens to CD4+ T cells. CD4+ T helper cells, in turn, use CD40L to license cross-presenting CD40+ Batf3+ dendritic cells to elicit a cytotoxic T cell response against neoantigen-expressing cells. Any break along this immunological chain reaction results in the escape of neoantigen-expressing cells. This study demonstrates the surprising, essential role of natural IgM as the initiator of a sequential signaling cascade involving multiple immune cell subtypes. This sequence is required to coordinate an adaptive immune response against neoantigen-expressing cells.

Keywords: Ly6C+ monocytes; XCR1+ Batf3+ dendritic cells; cancer; natural IgM; neoantigens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptive Immunity*
  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigens, Neoplasm / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / pathology
  • CD40 Ligand / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Dendritic Cells / pathology
  • Female
  • Immunoglobulin M / immunology*
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lymphocyte Activation
  • Male
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Monocytes / immunology
  • T-Lymphocytes, Helper-Inducer / immunology


  • Antigens, Neoplasm
  • Immunoglobulin M
  • CD40 Ligand