Update on Fc receptor-like (FCRL) family: new immunoregulatory players in health and diseases

ABSTRACT

Introduction: Fc receptor-like (FCRL) molecules, as recently identified members of the immunoglobulin superfamily (IgSF), are preferentially expressed by B-cells. They have variable number of extracellular immunoglobulin-like domains and cytoplasmic activating ITAMs and/or inhibitory ITIMs. FCRL1-5 are dominantly expressed in different stages of B-cells development. But, FCRL6 is preferentially expressed in different subsets of T-cells and NK cells. FCRL1-5 could regulate different features of B-cell evolution such as development, differentiation, activation, antibody secretion and isotype switching.

Areas covered: Improved understanding of FCRL expression may grant B-cells and finally its signaling pathways, alone or in cooperation with other signaling molecules, as interesting new targets for diagnostic, monitoring and immunotherapeutic modalities; although further investigations remain to be defined. Recent investigations on different family members of FCRL proteins have substantiated their differential expression on different tissues, malignancies, immune related disease and infectious diseases.

Expert opinion: FCRLs restricted expressions in normal B-cells and T-cell subsets accompanied with their overexpression in B-cell malignancies introduce them as logical candidates for the development of antibody- and cell-based immunotherapy approaches in B-cell malignancies, immune-mediated and infectious diseases. FCRLs would be applied as attractive and specific targets for immunodiagnostic approaches, clinical prognosis as well as disease monitoring of relevant patients.

KEYWORDS:

• FCRL
• B-cell
• malignancies
• autoimmune diseases
• infectious diseases
• signaling pathways
• immunotherapy approaches

Article highlights

• Fc receptor-like (FCRL) molecules, as recently identified members of the immunoglobulin superfamily (IgSF), are preferentially expressed by B-cells and some T-cell subsets including CD4⁺ T-cells, CD8⁺ T-cells, NK cells, and dysfunctional population of CD4⁺ regulatory T-cells (Tregs).

• In contrast to FCRL-6 which is preferentially expressed in different subsets of T-cells and NK cells, FCRL1-5 are dominantly expressed in different stages of B-cells development and could participate in differentiation, activation, antibody secretion and isotype switching of B-cells.

• The polymorphisms of FCRL genes, especially FCRL3 have been investigated in several autoimmune diseases and available data indicates that FCRL3 augments inhibition of Treg function and give them an exhausted memory phenotype with lower responsiveness to antigenic stimulation and reduced suppression capacity on effector T-cells which results in breaking of self-tolerance. These effects might be partially explained by the inhibiting effect of FCRL3 on TCR signaling in Treg cells in line with other negative regulator of Treg function, such as PD-1.

• The FCRL expression profile has been widely investigated in several B-cell malignancies, infectious diseases, as well as in some autoimmune diseases. Recent studies revealed that the expression of FCRLs is associated with dysfunctional immune cell responses which support the FCRLs participation in perturbed immunity.

• FCRLs restricted expression in normal B-cells accompany with their overexpression in B-cell malignancies and T-cell subsets, especially Treg, introduce them as logical candidates for development of antibody- and cell-based immunotherapy approaches in autoimmune diseases and B-cell malignancies.

• In addition FCRL molecules would be applied as attractive and specific targets for immunodiagnostic approaches, clinical prognosis as well as disease monitoring of relevant patients.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

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