Expression of the immunoregulatory molecule FcRH4 defines a distinctive tissue-based population of memory B cells

Abstract

The FcRH4 transmembrane molecule, a member of the Fc receptor homologue family, can potently inhibit B cell receptor (BCR) signaling. We show that cell surface expression of this immunoregulatory molecule is restricted to a subpopulation of memory B cells, most of which lack the classical CD27 marker for memory B cells in humans. The FcRH4+ and FcRH4− memory B cells have undergone comparable levels of immunoglobulin isotype switching and somatic hypermutation, while neither subpopulation expresses the transcription factors involved in plasma cell differentiation. The FcRH4+ memory cells are morphologically distinctive large lymphocytes that express the CD69, CD80, and CD86 cell activation markers. They are also shown to be poised to secrete high levels of immunoglobulins in response to stimulation with T cell cytokines, but they fail to proliferate in response either to BCR ligation or Staphylococcus aureus stimulation. A heightened expression of the CCR1 and CCR5 chemokine receptors may facilitate their preferential localization in lymphoid tissues near epithelial surfaces. Cell surface FcRH4 expression thus marks a unique population of memory B cells with distinctive morphology, functional capabilities, and tissue localization.

Defining origins of malignant B cells: a new circulating normal human IgM+D+ B-cell subset lacking CD27 expression and displaying somatically mutated IGHV genes as a relevant memory population

“…14 Isotype-switched CD27 Àve CD38 Àve FcRH4 þ B cells with a comparably low level of mutation have also been described in the tonsil, but these remain tissue localized and are not observed in the blood. 15 FcRH4, Fc receptor homolog 4, is a immunoregulatory molecule, 15 and based on these observations seemed to be a relevant marker for mutated CD27 Àve cells. However, normal circulating IgG þ CD27 Àve memory B cells lack FcRH4 expression, 10 indicating divergent origins from the tonsillar B-cell subset.…”

Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy

“…In contrast to peripheral blood, CD27 expression in tonsils does not strictly correlate with memory because a variable fraction of the Bm5Ј memory compartment does not express CD27, and the majority of GC cells also express CD27. Tissue memory B cells were additionally examined for the recently described FcRH-4 (23,24). Measurements of peripheral blood transitional cells were obtained from patients at multiple time points when B cells were detectable.…”

Ancient divergence of a complex family of immune-type receptor genes

“…The MDIR domains exhibit similarity to many pIgRs, and there is very distant similarity of the MDIR types III and IV domains to FcRHs, which likely function in B-cell regulation (Davis et al 2001(Davis et al , 2002bEhrhardt et al 2003Ehrhardt et al , 2005Leu et al 2005); however, the membrane and cytosolic features of MDIRs are generally more similar to those seen in CMRF-35/MAIR/CLM and FcRH molecules than to those of pIgR. Although similarity in expression profiles could potentially reveal relationships to the expression patterns of complex activating/inhibitory IgSF members found in other vertebrates, the only significant MDIR gene expression that we have observed to date is in the epigonal organ, which contains B and T lymphocytes, as well as appreciable numbers of myeloid cells, and lacks an equivalent tissue in other vertebrates (unpublished observation).…”