The Mertk receptor tyrosine kinase promotes T–B interaction stimulated by IgD B-cell receptor cross-linking
Introduction
Goat IgG anti-mouse IgD antibody (Ab) (GαmD) binds to B-cell membrane IgD and cross-links this B cell receptor (BCR), inducing T cell-independent B-cell activation, GamD internalization and processing, and presentation of Class II MHC-associated GamD-derived peptides to CD4+ T cells [1], [2]. The goat IgG-specific CD4+ T cells primed or activated by these B cells then secrete cytokines, including IL-4, and express surface molecules that activate newly generated B cells to proliferate and differentiate into Ab secreting cells [3]. Most initially activated B cells undergo apoptosis 2–5 days after injection [4]. Major findings that have been reported with this well-characterized model are summarized in Fig. 1 [5], [6], [7]. The IL-4 produced by T cells in this response is required for Ig isotype switching to IgE and suppresses complement-fixing isotypes (IgG2a and IgG3) [8], [9]. Studies with univalent F(ab') fragments of anti-IgD Ab and with mAbs that poorly crosslink IgD demonstrate that T-independent B cell activation is required to stimulate T cell activation and B cell antibody production [10]. Indeed, failure to activate B cells by this mechanism can induce Ag specific T-cell tolerance [11].
Mertk belongs to the TAM (Tyro-3, Axl, and Mertk) subfamily of receptor tyrosine kinases [12]. Mertk mediates the engulfment of apoptotic cells through the bridging molecules (growth-arrest-specific gene 6 (Gas6) or Protein S (ProS)), and promotes maturation of macrophages to a non-inflammatory phenotype [13], [14], [15]. Without Mertk, mice develop lupus-like autoimmune manifestations and retinal degeneration-associated blindness [13], [16]. Mertk is expressed on subpopulations of macrophages and dendritic cells [17] and is also found on certain B cells, where it is tightly regulated [18]. Mertk-deficient B cells are unresponsive to T-cell help in a chronic graft-versus-host disease (cGVHD) model [18], [19], yet the mechanisms whereby Mertk regulates B-cell function remain obscure.
To understand better how Mertk regulates B-cell responses, we chose the anti-IgD model because it allows in vivo evaluation of T-independent B cell activation by membrane IgD cross-linking, B cell Ag processing, B cell-dependent T cell activation, and T cell-dependent Ag production. We cross-linked B-cell IgD receptors with GαmD and studied the subsequent B-cell activation-induced immune responses. We report here that B cells lacking Mertk have a defect in activating T cells, and are associated with lower Ab production compared to B cells from WT mice.
Section snippets
Mice and reagents
C57BL/6J (B6; 6–8 weeks old; WT controls) and C57BL/6J Mertk deficient (Mertk-KO; 6–8 weeks old) mice were bred and maintained in our mouse colony. Experimental mice were sex and age matched. All mouse procedures followed the guidelines for the use of animals in research and were approved by the Institutional Animal Care and Use Committee of Temple University. Affinity-purified goat Ab specific for mouse IgD (GαmD) and monoclonal mouse IgG1 anti-mouse IgD (clone 1.3.7) were produced and tested
Mertk-KO mice exhibit significantly reduced responses to goat anti-mouse IgD cross-linking
We previously reported an intrinsic B-cell unresponsiveness to bm12 induced chronic GVHD from Mertk-KO mice [18], [19]. To further explore the function of Mertk on B cells, we injected Mertk-KO mice with GαmD and measured immunoglobulin levels compared to WT mice undergoing the same treatment. We therefore measured the serum level of total IgG with untreated mice serum as control. As expected, WT mice showed a dramatic increase of total IgG in the serum 10 days after GαmD injection. Mertk-KO
Discussion
Studies on the function of Mertk receptor tyrosine kinase have focused on apoptotic cell clearance and immune regulation through Mertk-bearing macrophages and DCs [12], [13], [21], [22], [23], [24]. We have noted expression and function of Mertk on certain B cells [18], [19]. In this report, we describe deficient antigen presentation by B cells from Mertk deficient mice. Similar to B cells from WT mice, B cells from Mertk-KO mice were activated and proliferated normally in response to membrane
Acknowledgments
This work was supported by grants from the NIAID (IU19AI082726) and NIH (AI097758) to PLC and by Arthritis Foundation Postdoctoral Fellowship Award and NIDDK (1K01DK095067-01A1) to WHS. FDF receives support from the U.S. Department of Veterans Affairs.
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