Regulation of the BCR signalosome by the class II peptide editor, H2-M, affects the development and repertoire of innate-like B cells
Debopam Ghosh,
Tho D. Pham,
Padma P. Nanaware,
Deepanwita Sengupta,
Lital N. Adler,
Caiyun G. Li,
Xiao He,
Mary E. O'Mara,
Aaron B. Kantor,
Khoa D. Nguyen,
Yang Yang,
Laurence C. Eisenlohr,
Peter E. Jensen,
Leonore A. Herzenberg,
Lawrence J. Stern,
Scott D. Boyd,
Eliver E.B. Ghosn,
Elizabeth D. Mellins
Affiliations
Debopam Ghosh
Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Corresponding author
Tho D. Pham
Department of Pathology, Stanford University, Stanford, CA 94305, USA
Padma P. Nanaware
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Deepanwita Sengupta
Department of Biology, Stanford University, Stanford, CA 94305, USA
Lital N. Adler
Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
Caiyun G. Li
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA
Xiao He
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA
Mary E. O'Mara
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Aaron B. Kantor
Department of Genetics, Stanford University, Stanford, CA 94305, USA
Khoa D. Nguyen
Department of Pathology, Stanford University, Stanford, CA 94305, USA
Yang Yang
Department of Genetics, Stanford University, Stanford, CA 94305, USA
Laurence C. Eisenlohr
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Peter E. Jensen
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA
Leonore A. Herzenberg
Department of Genetics, Stanford University, Stanford, CA 94305, USA
Lawrence J. Stern
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Scott D. Boyd
Department of Pathology, Stanford University, Stanford, CA 94305, USA
Eliver E.B. Ghosn
Departments of Medicine and Pediatrics, Lowance Center for Human Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA; Corresponding author
Elizabeth D. Mellins
Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Corresponding author
Summary: The non-classical Major Histocompatibility Complex class II (MHCII) protein, H2-M, edits peptides bound to conventional MHCII in favor of stable peptide/MHCII (p/MHCII) complexes. Here, we show that H2-M deficiency affects B-1 cell survival, reduces cell renewal capacity, and alters immunoglobulin repertoire, allowing for the selection of cells specific for highly abundant epitopes, but not low-frequency epitopes. H2-M-deficient B-1 cells have shorter CDR3 length, higher content of positively charged amino acids, shorter junctional regions, less mutation frequency, and a skewed clonal distribution. Mechanistically, H2-M loss reduces plasma membrane p/MHCII association with B cell receptors (BCR) on B-1 cells and diminishes integrated BCR signal strength, a key determinant of B-1 cell selection, maturation, and maintenance. Thus, H2-M:MHCII interaction serves as a cell-intrinsic regulator of BCR signaling and influences the selection of the B-1 cell clonal repertoire.
