Related Experiment Video
Updated: Jun 14, 2026
12:04
Engineering Oncogenic Heterozygous Gain-of-Function Mutations in Human Hematopoietic Stem and Progenitor Cells
Published on: March 10, 2023
Deleterious germline CARD11 gain-of-function variants alter human B-cell and CD4+ T-cell differentiation and function
Tina Nguyen1,2, Melissa A Kallarakal3, Jackie L Ludgate4
1Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
Clinical and Experimental Immunology
|June 12, 2026
Summary
Gain-of-function variants in CARD11 impact both B and T cell functions, revealing new insights into immune disorders and potential therapeutic targets for CARD11-related diseases.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- CARD11 is a crucial scaffold protein in hematopoietic cells, regulating key signaling pathways in B and T cells.
- Gain-of-function (GOF) CARD11 variants cause immune dysfunction, leading to infections, B-cell expansion, and lymphoma risk.
- Previous research focused on B-cell defects, leaving T-cell contributions of CARD11 GOF variants unexplored.
Purpose of the Study:
- To investigate the impact of increased CARD11 activity on adaptive lymphocyte development, maturation, activation, differentiation, and effector functions.
- To analyze ex vivo immunophenotyping and in vitro data from individuals with monoallelic CARD11 GOF variants.
Main Methods:
- Detailed ex vivo immunophenotyping of adaptive lymphocytes.
- In vitro functional assays.
- Analysis of individuals with monoallelic CARD11 GOF variants.
Main Results:
- CARD11 is intrinsically required for the activation, differentiation, and effector functions of human naive B cells.
- Contrary to prior studies, CARD11 activity is essential for CD4+ T-cell homeostasis.
- CARD11 plays a significant role in both humoral immunity and T-cell function.
Conclusions:
- Findings elucidate disease pathogenesis mechanisms for CARD11 GOF and loss-of-function (LOF) variants.
- The study identifies potential therapeutic strategies for CARD11 GOF-related disorders.
- Highlights the dual role of CARD11 in both B and T cell-mediated immunity.
Related Concept Videos
01:12Loss of Tumor Suppressor Gene Functions
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:22T Cell Activation and Clonal Selection
T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
Naive T cells that have not yet encountered an antigen express two primary CD...
Naive T cells that have not yet encountered an antigen express two primary CD...
02:23Abnormal Proliferation
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
01:24T Cell Types and Functions
When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
01:22iPS Cell Differentiation
The ability of induced pluripotent stem cells or iPSCs to differentiate into most body cell types has stimulated repair and regenerative medicine research over the past few decades. iPSC-derived blood cells, hepatocytes, beta islet cells, cardiomyocytes, neurons, and other cell types can repair injuries or regenerate damaged tissue in diseases such as diabetes and neurodegenerative disorders.