Wiskott-Aldrich Syndrome Protein-Deficient Mice Reveal a Role for WASP in T but Not B Cell Activation

Key Points Mice lacking both WASP and N-WASP in B lymphocytes have impaired response to T-cell-dependent antigens and defective B-cell activation. Deletion of N-WASP in B cells attenuates autoimmunity in WASP-deficient mice.

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T Cell Accumulation in B Cell Follicles Is Regulated by Dendritic Cells and Is Independent of B Cell Activation

Journal of Experimental Medicine ◽

10.1084/jem.20021750 ◽

2003 ◽

Vol 197 (2) ◽

pp. 195-206 ◽

Cited By ~ 70

Author(s):

Simon Fillatreau ◽

David Gray

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

B Cell Activation ◽

Cell Accumulation ◽

Antigen Presenting ◽

Deficient Mice

We investigated the mechanism of CD4 T cell accumulation in B cell follicles after immunization. Follicular T cell numbers were correlated with the number of B cells, indicating B cell control of the niche that T cells occupy. Despite this, we found no role for B cells in the follicular migration of T cells. Instead, T cells are induced to migrate into B cell follicles entirely as a result of interaction with dendritic cells (DCs). Migration relies on CD40-dependent maturation of DCs, as it did not occur in CD40-deficient mice but was reconstituted with CD40+ DCs. Restoration was not achieved by the activation of DCs with bacterial activators (e.g., lipopolysaccharide, CpG), but was by the injection of OX40L–huIgG1 fusion protein. Crucially, the up-regulation of OX40L (on antigen-presenting cells) and CXCR-5 (on T cells) are CD40-dependent events and we show that T cells do not migrate to follicles in immunized OX40-deficient mice.

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Critical Role for CD81 in B Cell Activation.

Blood ◽

10.1182/blood.v110.11.1342.1342 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1342-1342

Author(s):

Mrinmoy Sanyal ◽

Rosemary Fernandez ◽

Shoshana Levy

Keyword(s):

B Cells ◽

B Cell ◽

Cell Activation ◽

Cell Function ◽

Calcium Influx ◽

Critical Role ◽

B Cell Lymphoma ◽

Free Calcium ◽

B Cell Activation ◽

Deficient Mice

Abstract CD81 is a component of the CD19/CD21 signaling complex in B cells. CD81 was originally discovered as target of an anti-proliferative antibody in a human B cell lymphoma. However, the exact role of CD81 in B cell function is not known. Here we studied B cells from CD81 knockout mice. We demonstrate that upon BCR induction these B cells flux higher intracellular free calcium ion; increase the phosphorylation of BCR-related proximal and distal substrates and increase their proliferation. Similarly, polyclonal activation of CD81-deficient B cells with LPS induced increased proliferation and antibody secretion. Consistent with these intrinsic B cell capabilities, CD81-deficient mice mounted significantly higher immune response upon antigenic stimulation. In addition, bone marrow perisinusoidal B cells (IgM+IgD+) capable of mounting T-independent immune responses against blood-borne pathogens were over represented in CD81-deficient mice. These cells also displayed increased calcium influx kinetics as splenic B cells and produced higher amounts of antibody after polyclonal stimulation. Taken together, these results suggest that CD81 is involved in suppressing B cell activation.

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Perturbation of B cell activation in SLAM-associated protein-deficient mice is associated with changes in gammaherpesvirus latency reservoirs

The Journal of Immunology ◽

10.4049/jimmunol.178.11.7487 ◽

2007 ◽

Vol 178 (11) ◽

pp. 7487.1-7487

Author(s):

I.-J. Kim ◽

C. E. Burkum ◽

T. Cookenham ◽

P. L. Schwartzberg ◽

D. L. Woodland ◽

...

Keyword(s):

B Cell ◽

Cell Activation ◽

B Cell Activation ◽

Deficient Mice

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Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs

The Journal of Immunology ◽

10.4049/jimmunol.178.3.1692 ◽

2007 ◽

Vol 178 (3) ◽

pp. 1692-1701 ◽

Cited By ~ 8

Author(s):

In-Jeong Kim ◽

Claire E. Burkum ◽

Tres Cookenham ◽

Pamela L. Schwartzberg ◽

David L. Woodland ◽

...

Keyword(s):

B Cell ◽

Cell Activation ◽

B Cell Activation ◽

Deficient Mice

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Wiskott-Aldrich syndrome protein deficiency leads to reduced B-cell adhesion, migration, and homing, and a delayed humoral immune response

Blood ◽

10.1182/blood-2004-03-1003 ◽

2005 ◽

Vol 105 (3) ◽

pp. 1144-1152 ◽

Cited By ~ 91

Author(s):

Lisa Westerberg ◽

Malin Larsson ◽

Samantha J. Hardy ◽

Carmen Fernández ◽

Adrian J. Thrasher ◽

...

Keyword(s):

Immune Response ◽

B Cells ◽

B Cell ◽

Humoral Immune Response ◽

Wiskott Aldrich Syndrome ◽

Humoral Immune ◽

Germinal Center Reaction ◽

Syndrome Protein ◽

Deficient Mice

Abstract The Wiskott-Aldrich syndrome protein (WASp) is mutated in the severe immunodeficiency disease Wiskott-Aldrich syndrome (WAS). The function of B cells and the physiologic alterations in WAS remain unclear. We show that B cells from WAS patients exhibited decreased motility and had reduced capacity to migrate, adhere homotypically, and form long protrusions after in vitro culture. WASp-deficient murine B cells also migrated less well to chemokines. Upon antigen challenge, WASp-deficient mice mounted a reduced and delayed humoral immune response to both T-cell–dependent and –independent antigens. This was at least in part due to deficient migration and homing of B cells. In addition, the germinal center reaction was reduced in WASp-deficient mice. Thus, WASp is crucial for optimal B-cell responses and plays a pivotal role in the primary humoral immune response.

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Galectin-9 regulates the threshold of B cell activation and autoimmunity

eLife ◽

10.7554/elife.64557 ◽

2021 ◽

Vol 10 ◽

Author(s):

Logan K Smith ◽

Kareem Fawaz ◽

Bebhinn Treanor

Keyword(s):

B Cell ◽

Regulatory Network ◽

Cell Activation ◽

Critical Role ◽

Peripheral Tolerance ◽

B Cell Activation ◽

Cell Compartment ◽

Cell Responses ◽

Self Antigen ◽

Deficient Mice

Despite the mechanisms of central and peripheral tolerance, the mature B cell compartment contains cells reactive for self-antigen. How these cells are poised not to respond and the mechanisms that restrain B cell responses to low-affinity endogenous antigens are not fully understood. Here, we demonstrate a critical role for the glycan-binding protein galectin-9 in setting the threshold of B cell activation and that loss of this regulatory network is sufficient to drive spontaneous autoimmunity. We further demonstrate a critical role for galectin-9 in restraining not only conventional B-2 B cells, but also innate-like B-1a cells. We show that galectin-9-deficient mice have an expanded population of B-1a cells and increased titers of B-1a-derived autoantibodies. Mechanistically, we demonstrate that galectin-9 regulates BCR and distinct TLR responses in B-1a cells, but not B-1b cells, by regulating the interaction between BCR and TLRs with the regulatory molecules CD5 and CD180, respectively. In the absence of galectin-9, B-1a cells are more readily activated and secrete increased titers of autoantibodies that facilitate autoantigen delivery to the spleen, driving autoimmune responses.

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Absence of CD81 Paradoxically Results in a Hyper-IgM and IgG Response to T-Independent Antigens.

Blood ◽

10.1182/blood.v108.11.1719.1719 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1719-1719

Author(s):

Mrinmoy Sanyal ◽

Tsipi Shoham ◽

Rosemary Fernandez ◽

Shoshana Levy

Keyword(s):

B Cells ◽

B Cell ◽

Cell Activation ◽

Cell Receptor ◽

Cellular Interactions ◽

B Cell Activation ◽

Signaling Complex ◽

Hyper Igm ◽

Deficient Mice

Abstract The tetraspanin CD81 is required for numerous biological functions including fertilization, infection, cell migration and cellular interactions in the nervous and immune systems. In B cells CD81 is a component of the CD19/CD21 signaling complex. CD81 was shown to facilitate the redistribution of the B cell receptor (BCR) complex and CD21 into lipid rafts in response to co-engagement, and to modulate BCR signaling. In addition, CD81-deficient mice express low levels of cell surface CD19, thereby potentially altering signaling by the CD19/CD21 co-receptor complex. Interestingly, the onset of CD81 expression coincides with the onset of CD19 expression during B cell development. The foregoing observations suggest that CD81 might reduce the in vivo response of B cells to antigenic stimulation. To test this hypothesis we compared the response of CD81-deficient and wild type mice to T-independent (TNP-LPS) and T-dependent (TNP-KLH) antigens. Surprisingly, CD81-deficient mice mounted significantly higher IgM responses against both types of antigens. Moreover, the IgG response of CD81-deficient mice was stronger and persistent in response to T-independent antigen. We further found that CD81-deficient mice have an increase in bone marrow perisinusoidal B cells (IgM+IgD+). These cells are primarily responsible for mounting T-independent immune responses against blood-borne pathogens. In addition, CD81-deficient spleenic B cells have an intrinsic ability to produce higher amounts of IgM. These surprising results suggest that CD81 is involved in modulating B cell activation, particularly in response to infection.

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c-Abl-deficient mice exhibit reduced numbers of peritoneal B-1 cells and defects in BCR-induced B cell activation

International Immunology ◽

10.1093/intimm/dxp006 ◽

2009 ◽

Vol 21 (4) ◽

pp. 403-414 ◽

Cited By ~ 7

Author(s):

R. A. Liberatore ◽

S. P. Goff

Keyword(s):

B Cell ◽

Cell Activation ◽

B Cell Activation ◽

Deficient Mice

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γδ T cells affect IL-4 production and B-cell tolerance

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1415107111 ◽

2014 ◽

Vol 112 (1) ◽

pp. E39-E48 ◽

Cited By ~ 22

Author(s):

Yafei Huang ◽

Ryan A. Heiser ◽

Thiago O. Detanico ◽

Andrew Getahun ◽

Greg A. Kirchenbaum ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Cell Activation ◽

Γδ T Cells ◽

T Cell Subsets ◽

Cell Tolerance ◽

B Cell Activation ◽

B Cell Tolerance ◽

Deficient Mice ◽

Αβ T Cells

γδ T cells can influence specific antibody responses. Here, we report that mice deficient in individual γδ T-cell subsets have altered levels of serum antibodies, including all major subclasses, sometimes regardless of the presence of αβ T cells. One strain with a partial γδ deficiency that increases IgE antibodies also displayed increases in IL-4–producing T cells (both residual γδ T cells and αβ T cells) and in systemic IL-4 levels. Its B cells expressed IL-4–regulated inhibitory receptors (CD5, CD22, and CD32) at diminished levels, whereas IL-4–inducible IL-4 receptor α and MHCII were increased. They also showed signs of activation and spontaneously formed germinal centers. These mice displayed IgE-dependent features found in hyper-IgE syndrome and developed antichromatin, antinuclear, and anticytoplasmic autoantibodies. In contrast, mice deficient in all γδ T cells had nearly unchanged Ig levels and did not develop autoantibodies. Removing IL-4 abrogated the increases in IgE, antichromatin antibodies, and autoantibodies in the partially γδ-deficient mice. Our data suggest that γδ T cells, controlled by their own cross-talk, affect IL-4 production, B-cell activation, and B-cell tolerance.

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