CD4+ T Cell Dependent B Cell Recovery and Function After Autologous Hematopoietic Stem Cell Transplantation.

Clarissa Heck,Lars Bullinger,Il-Kang Na,Axel Nogai,Leif G Hanitsch,Marco Frentsch,Igor-Wolfgang Blau,Friedrich Wittenbecher,Carmen Scheibenbogen,Eva M Kaebisch,Sophie Steiner,Philipp Le Coutre

doi:10.3389/fimmu.2021.736137

Abstract

IntroductionHigh-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) represents a standard treatment regime for multiple myeloma (MM) patients. Common and potentially fatal side effects after auto-HSCT are infections due to a severely compromised immune system with hampered humoral and cellular immunity. This study delineates in depth the quantitative and functional B cell defects and investigates underlying extrinsic or intrinsic drivers.MethodsPeripheral blood of MM patients undergoing high-dose chemotherapy and auto-HSCT (before high-dose chemotherapy and in early reconstitution after HSCT) was studied. Absolute numbers and distribution of B cell subsets were analyzed ex vivo using flow cytometry. Additionally, B cell function was assessed with T cell dependent (TD) and T cell independent (TI) stimulation assays, analyzing proliferation and differentiation of B cells by flow cytometry and numbers of immunoglobulin secreting cells in ELISpots.ResultsQuantitative B cell defects including a shift in the B cell subset distribution occurred after auto-HSCT. Functionally, these patients showed an impaired TD as well as TI B cell immune response. Individual functional responses correlated with quantitative alterations of CD19+, CD4+, memory B cells and marginal zone-like B cells. The TD B cell function could be partially restored upon stimulation with CD40L/IL-21, successfully inducing B cell proliferation and differentiation into plasmablasts and immunoglobulin secreting cells.ConclusionQuantitative and functional B cell defects contribute to the compromised immune defense in MM patients undergoing auto-HSCT. Functional recovery upon TD stimulation and correlation with CD4+ T cell numbers, indicate these as extrinsic drivers of the functional B cell defect. Observed correlations of CD4+, CD19+, memory B and MZ-like B cell numbers with the B cell function suggest that these markers should be tested as potential biomarkers in prospective studies.

Highlights

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation represents a standard treatment regime for multiple myeloma (MM) patients
Quantitative and functional B cell defects occur after high-dose chemotherapy and auto-HSCT
Correlations of the TD B cell function with CD4+ T cell counts highlight the restorative effect of the applied stimulants CD40L and IL-21

Summary

Introduction

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) represents a standard treatment regime for multiple myeloma (MM) patients. B cells make up an essential part of the adaptive immune system as drivers of humoral immune responses. Two different pathways leading to B cell activation and thereby the induction of antibody synthesis are often described. These are the T cell dependent (TD from thymus dependent) and the T cell independent (TI from thymus independent) activation. TI B cell activation is prompted by mitogens like lipopolysaccharides and bacterial DNA or by polysaccharides on encapsulated bacteria, which activate B cells by crosslinking B cell receptors (BCR). The result is a fast and IgM driven B cell response, eliminating pathogens that would otherwise escape a humoral reaction due to the capsule protecting them from phagocytosis by APCs [4]

Objectives

Methods

Results

Discussion

Conclusion