Fc receptor-like 4 and 5 define human atypical memory B cells

Abstract

Atypical memory B cells accumulate in chronic infections and autoimmune conditions, and commonly express FCRL4 and FCRL5, respective IgA and IgG receptors. We characterized memory cells from tonsils based on both FCRL4 and FCRL5 expression, defining three subsets with distinct surface proteins and gene expression. Atypical FCRL4+FCRL5+ memory cells had the most discrete surface protein expression and were enriched in cell adhesion pathways, consistent with functioning as tissue-resident cells. Atypical FCRL4-FCRL5+ memory cells expressed transcription factors and immunoglobulin genes that suggest poised differentiation into plasma cells. Accordingly, the FCRL4-FCRL5+ memory subset was enriched in pathways responding to endoplasmic reticulum stress and IFN-γ. We reconstructed ongoing B cell responses as lineage trees, providing crucial in vivo developmental context. Each memory subset typically maintained its lineage, denoting mechanisms enforcing their phenotypes. Classical FCRL4-FCRL5- memory cells were infrequently detected in lineage trees, suggesting the majority were in a quiescent state. FCRL4-FCRL5+ cells were the most represented memory subset in lineage trees, indicating robust participation in ongoing responses. Together these differences suggest FCRL4 and FCRL5 are unlikely to be passive markers but rather active drivers of human memory B cell development and function.

Single-Cell RNA Sequencing Reveals Tumor Microenvironment Remodeling after Neoadjuvant Immunotherapy in Non-small Cell Lung Cancer

“…Although memory B cells in general decreased following combined treatment, the FCRL4+FCRL5+ B cells (B4-FCRL4), de ned as "atypical memory B cells" 55 , were signi cantly increased in MPR patients but not NMPR patients (Fig. 4b,c).…”

“…4b,c). The FCRL4 and FCRL5 genes encode the Fc receptors for IgA and IgG, respectively, and are drivers of human memory B-cell activations 55 . B cells expressing FCRL4 have been previously reported to be associated with in ammation in rheumatoid arthritis 56 and viral infections 57 .…”

Lymphocytes sense antibodies through human FCRL proteins: Emerging roles in mucosal immunity

“…In healthy subjects, strikingly similar memory B cells expressing FCRL4, FCRL5, or both exist in mucosa‐associated lymphoid tissues such as tonsils 26,27,55 . We recently reported that FCRL4 and FCRL5 together define unexpectedly well developmentally stable subsets of tonsillar memory B cells 27 . Based on gene expression, surface proteins, and reconstruction of in vivo developmental paths, we concluded that the FCRL4 − FCRL5 + subset actively participates in ongoing responses, and is poised to differentiate into plasma cells, whereas the FCRL4 + FCRL5 + subset displays marks of tissue residency (Fig.…”

“…In contrast, FCRL4 was so far found expressed by a subset of memory B cells, which in healthy individuals reside in mucosa‐associated lymphoid tissues 26 . FCRL5 is expressed by memory B cells that are poised to differentiate into plasmablasts, 27–30 and uniquely among FCRL is highly expressed by plasma cells 19 . Memory B cells from healthy tonsils and blood of SLE patients can co‐express FCRL4 and FCRL5 27,28 .…”

“…2). The FCRL4 + FCRL5 + subset also expressed FCRL3 mRNA, potentially making these cells the subject of complex regulation by multiple types of antibodies 27 …”