Negative Regulation of Humoral Immunity Due to Interplay between the SLAMF1, SLAMF5, and SLAMF6 Receptors.

Ninghai Wang,Cox Terhorst,Burcu Yigit,Michael S O’Keeffe,Hui Zhao,Peter J Halibozek,Arlene Sharpe,Peter Sage

doi:10.3389/fimmu.2015.00158

Ninghai Wang, Cox Terhorst + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2015.00158

Copy DOI

Abstract

Whereas the SLAMF-associated protein (SAP) is involved in differentiation of T follicular helper (Tfh) cells and antibody responses, the precise requirements of SLAMF receptors in humoral immune responses are incompletely understood. By analyzing mice with targeted disruptions of the Slamf1, Slamf5, and Slamf6 genes, we found that both T-dependent and T-independent antibody responses were twofold higher compared to those in single knockout mice. These data suggest a suppressive synergy of SLAMF1, SLAMF5, and SLAMF6 in humoral immunity, which contrasts the decreased antibody responses resulting from a defective GC reaction in the absence of the adapter SAP. In adoptive co-transfer assays, both [Slamf1 + 5 + 6]−/− B and T cells were capable of inducing enhanced antibody responses, but more pronounced enhancement was observed after adoptive transfer of [Slamf1 + 5 + 6]−/− B cells compared to that of [Slamf1 + 5 + 6]−/− T cells. In support of [Slamf1 + 5 + 6]−/− B cell intrinsic activity, [Slamf1 + 5 + 6]−/− mice also mounted significantly higher antibody responses to T-independent type 2 antigen. Furthermore, treatment of mice with anti-SLAMF6 monoclonal antibody results in severe inhibition of the development of Tfh cells and GC B cells, confirming a suppressive effect of SLAMF6. Taken together, these results establish SLAMF1, SLAMF5, and SLAMF6 as important negative regulators of humoral immune response, consistent with the notion that SLAM family receptors have dual functions in immune responses.

Highlights

The humoral immune response is crucial for protecting individuals from many infections and eliminating foreign substances
THE COMBINED ABSENCE OF SLAMF1, SLAMF5, AND SLAMF6 ENHANCES ANTIGEN SPECIFIC PLASMA CELL EXPANSION, BUT HAS NO EFFECT ON THE DEVELOPMENT OF GC B CELLS, TFH CELLS, OR T FOLLICULAR REGULATORY (TFR) CELLS As strong humoral immune responses, characterized by GC formation and long-lived plasma and memory B cells, are dependent on help provided by CD4+ T follicular helper (Tfh) cells [4, 5, 48], we examined whether enhanced T-cell dependent antibody responses in Slamf[1 + 5 + 6]−/− mice are correlated with an increase in Tfh cell differentiation and higher germinal center responses after immunization with NP-OVA
signaling lymphocytic activation molecule family (SLAMF)-associated protein (SAP) has been proven to bind to immunoreceptor tyrosine-based switch motif (ITSM) in most SLAMF receptors upon ligand stimulation, how these receptors function in the presence and absence of SAP is poorly understood, in B cells

Summary

Introduction

The humoral immune response is crucial for protecting individuals from many infections and eliminating foreign substances. In T-independent immunity, the antibody response occurs directly after B cell activation in T cell deficient mice. Tfh development is highly dependent on B cell responses, as Tfh cells are not found in B cell deficient mice [7, 10, 11]. These findings indicate that, through their interaction, GC B cells and Tfh cells reciprocally provide each other with signaling for survival, proliferation, and differentiation

Methods

Results

Conclusion