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

Abstract

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.

Human and mouse transcriptome profiling identifies cross-species homology in pulmonary and lymph node mononuclear phagocytes

“…DCs are potent antigen-presenting cells that link innate and adaptive immunity. In the periphery, DCs can acquire pathogens, traffic through lymphatic vessels to draining LNs, and present exogenous antigens to cognate T cells, precipitating adaptive immunity 11,24,25,26,27 . In mice, there are two main DC types referred to as Batf3 + DC1 and Irf4 +…”

Both maternal and newborn IgMs inhibit influenza virus-induced hemagglutination in vitro

“…IgM and other immunoglobulin isotypes are produced even before overt exposure to antigen, constituting the so-called natural antibodies [21]. Thus, immunoglobulins are found in human cord blood and in mice that have been kept in germfree con-ditions with minimal exposure to external antigens [22][23][24]. Therefore, in a normal, non-infected neonate the IgM Abs are predominately not stimulated by foreign Ags (excepting the possibility of Abs developed against maternally transferred Ags) [25].…”

Claudia Jakubzick: Work hard, play hard

“…Immunoglobulins form an immune complex with neoantigens located on the surface of precancerous cells, even in the absence of PAMPs or DAMPs. This tags precancerous cells for clearance by macrophages and activates antigen-presenting cells to present mutated self-antigens as immunogens, promoting adaptive immunity (Atif et al, 2018). Our studies, if fruitful, can lead to the development of new immunotherapies for cancer—but understanding how the system works at a fundamental level is the main goal.…”