Acute and Chronic B Cell Depletion Disrupts CD4+ and CD8+ T Cell Homeostasis and Expansion during Acute Viral Infection in Mice

Abstract

B cells provide humoral protection against pathogens and promote cellular immunity through diverse nonclassical effector functions. To assess B cell function in promoting T cell homeostasis, mature B cells were either acutely or chronically depleted in mice using CD20 mAb. Acute B cell depletion in either 2- or 4-mo-old mice significantly reduced spleen and lymph node CD4+ and CD8+ T cell numbers, including naive, activated, and Foxp3+CD25+CD4+ regulatory T cell subsets. The numbers of IFN-γ– and TNF-α–producing T cells were also significantly reduced. Chronic B cell depletion for 6 mo in aged naive mice resulted in a 40–70% reduction in activated CD4+ and CD8+ T cell numbers and 20–50% reductions in IFN-γ–producing T cells. Therefore, B cells were necessary for maintaining naive CD4+ and CD8+ T cell homeostasis for subsequent optimal T cell expansion in young and old mice. To determine the significance of this finding, a week of B cell depletion in 4-mo-old mice was followed by acute viral infection with lymphocytic choriomeningitis virus Armstrong. Despite their expansion, activated and cytokine-producing CD4+ and CD8+ T cell numbers were still significantly reduced 1 wk later. Moreover, viral peptide-specific CD4+ and CD8+ T cell numbers and effector cell development were significantly reduced in mice lacking B cells, whereas lymphocytic choriomeningitis virus titers were dramatically increased. Thus, T cell function is maintained in B cell–depleted mice, but B cells are required for optimal CD4+ and CD8+ T cell homeostasis, activation, and effector development in vivo, particularly during responses to acute viral infection.

B-Cell Depletion Promotes Aortic Infiltration of Immunosuppressive Cells and Is Protective of Experimental Aortic Aneurysm

“…Therefore, we quantified regulatory T cells (Tregs) in aorta and spleen using flow cytometry. As reported before 22 , absolute Treg number, but not the proportion of Treg (expressed as percentage of CD4+ T cells) was significantly lower in spleen following anti-CD20-mediated B cell depletion (Figure 6A). Staining of aortic cross-sections with CD3ε and FoxP3 antibodies demonstrated presence of Tregs in aortas of control antibody and anti-CD20 antibody treated mice (Figure 6B).…”

“…In the current study, we created B cell deficiency in mature WT mice by using anti-CD20 antibody which affected the homeostasis of T cells, primarily by reducing T cell number including Tregs in spleen as demonstrated by us and also reported previously by Lykken et al 22 Interestingly, IDO expressing pDC number was significantly increased in various tissues of B cell depleted mice. Moreover, B cell depletion has also been shown to improve endothelial function and reduce systemic inflammation in patients with rheumatoid arthritis 35 .…”

The molecular signature of murine T cell homeostatic proliferation reveals both inflammatory and immune inhibition patterns

“…Of note in this regard, CD4 + T regulatory cells, like CD4 − CD8 − TCRαβ + T cells, also manifest a high rate of homeostatic proliferation (K. A. F. unpublished observations) and express many of the same effector and inhibitory proteins as CD4 − CD8 − TCRαβ + T cells [72]. Hence, our observations regarding the gene expression changes in homeostatically expanding CD8 + T cells may also apply to CD4 + T cells and, potentially to B cells, as it was recently observed that immunosuppressive IL-10-producing B cells preferentially repopulate the B cell pool following depletion with anti-CD20 Rituximab [73]. …”

X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis

“…23,24 Emerging paradigms reveal many non-antibody-dependent functions of B cells that could play important roles in atherosclerosis. [25][26][27] We and others have shown follicular B2 cell interactions with CD4 + T cells, antagonized by marginal zone B2 cells, promote pathogenic T cell responses in the atherosclerotic setting. [28][29][30][31][32][33] Few models have, therefore, addressed the specific role of antibodies in isolation without impacting on other B cell functions.…”