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Identification of the Fc-alpha/mu receptor in Xenopus provides insight into the emergence of the poly-Ig receptor (pIgR) and mucosal Ig transport.

ABSTRACT: The polyimmunoglobulin receptor (pIgR) transcytoses J chain-containing antibodies through mucosal epithelia. In mammals, two cis-duplicates of PIGR, FCMR, and FCAMR, flank the PIGR gene. A PIGR duplication is first found in amphibians, previously annotated as PIGR2 (herein xlFCAMR), and is expressed by APCs. We demonstrate that xlFcamR is the equivalent of mammalian FcamR. It has been assumed that pIgR is the oldest member of this family, yet our data could not distinguish whether PIGR or FCAMR emerged first; however, FCMR was the last family member to emerge. Interestingly, bony fish "pIgR" is not an orthologue of tetrapod pIgR, and possibly acquired its function via convergent evolution. PIGR/FCAMR/FCMR are members of a larger superfamily, including TREM, CD300, and NKp44, which we name the "double-disulfide Ig superfamily" (ddIgSF). Domains related to each ddIgSF family were identified in cartilaginous fish (sharks, chimeras) and encoded in a single gene cluster syntenic to the human pIgR locus. Thus, the ddIgSF families date back to the earliest antibody-based adaptive immunity, but apparently not before. Finally, our data strongly suggest that the J chain arose in evolution only for Ig multimerization. This study provides a framework for further studies of pIgR and the ddIgSF in vertebrates.

SUBMITTER: Flowers EM

PROVIDER: S-EPMC8563443 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Altered Ig levels and antibody responses in mice deficient for the Fc receptor for IgM (Fc?R).

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Project description:The pioneering design of chimeric antigen receptors T-cells (CAR-T) therapy has revolutionized treatments of refractory lymphomas and demonstrated the potential in reprogramming the immune system. Nonetheless, exhaustion, cytotoxicity and suppressive tumor microenvironment limit their efficacy in solid tumors. Moreover, the high sensitivity f CART cells dictate directing it against antigens exclusively expressed on tumor cells. Recently, we characterized a novel subset of tumor-infiltrating CD4 + T-cells that express the high-affinity FcγRI receptor and are capable of antibody-mediated cell cytotoxicity. Here, we provide further analysis of their biology and prevalence in human diseases. We also provide evidences for the presence of CD8 + T cells expressing FcγRI in tumors. While endogenous FcγRI is expressed on exhausted and non-proliferative T cells, ectopic expression in naïve T cells endow them with ADCC capacities. Based on the FcγRI structure, we engineered a novel receptor, allowing T-cells to target tumor cells using antibody intermediates, without the need of TCR recognition. Antibodies provides an ideal mean to discriminate between cells that express high and physiological levels of antigens. Modifications to FcγRI signaling can tune the activation threshold required to elicit T cell cytotoxicity. Here, we further demonstrate the principles and considerations underlying the improvement of the signals transmitted through it. Overall, this work describes the benefits of separating the antigen-binding receptor from the signaling chain and suggests FcRI as a scaffold for cell therapy to overcome CAR T limitations in the treatment of solid tumors.

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