Regulation of many immune response genes depend on a 10 bp DNA sequence termed kappaB. This sequence is bound by a family of protein factors related to the Rel oncogene. The prototype transcription complex binding to the sequence, termed NF-kappaB, has been conventionally defined as a heterodimer between a P50 DNA binding protein and a P65 (RelA) activation protein that is typically sequestered in the cytoplasm by a protein called I-kappaB. Following certain types of stimulation to the cell, a specific protein kinase complex called I-kappaB kinase causes the phosphorylation of I-kappaB followed by its ubiquitination and degradation. Among the stimuli that can release NF-kappaB is the triggering of the T cell receptor (TCR) or B cell receptor (BCR) by antigen during an immune response. However, this transcription factor plays a role in the induction of diverse sets of genes throughout the body in response to hundreds of different inducers. While studying a rare clinical condition of immunodeficiency, We have also discovered the first germline mutation in CARD11, a protein that forms a vital signaling link between the antigen receptor in both B and T lymphocytes, in one family with congenital lymphoid hyperplasia first reported in The New England Journal of Medicine in 1971 as well as in a child adopted from China in a second family. The affected family members exhibit excessive accumulation and defective differentiation of B lymphocytes but not T lymphocytes. The dominant missense mutations identified will constitutively activate NF-kappaB in both B and T cells contributing to downstream proliferation in B cells. However,it causes apparent non-responsivenes or anergy in T cells resulting in poor IL-2 production and proliferation. Thus, we have identified the underlying genetic cause of this hereditary B cell disorder and have uncovered a potential molecular explanation for why CARD11 mutations may predispose to B but not T lymphoid malignancies. This can be understood in terms of the 2 signal model in which T lymphocytes require antigen receptor(signal 1) as well as costimulatory (signal 2)both required for T cell proliferation, whereas the provision solely of signal 1 leads to poor responsiveness or anergy. We observed this phenomenon in our patients, since E127G CARD11 causes internal constitutive activation of NF-kappaB, an important feature component of signal 1, in the absence of a concomitant signal 2. In contrast, B cell proliferation can be triggered by BCR crosslinking alone, which is mimicked by mutant CARD11-driven NF-kappaB activity. We posit that a chronic TCR-like signal 1 provided through mutant CARD11 can be converted to a proliferative signal for the patients T cells in vivo when proper costimulation (signal 2) is provided by professional antigen presenting cells. Defects in T cell help to B cells, related to T cell hyporesponsiveness, may partly explain the paucity of germinal centers and autoimmune manifestations in these patients. On the other hand, deficiencies in T cell-independent humoral responses to polysaccharide antigens also point to intrinsic defects in B cell signaling and effector function with E127G CARD11 present. Our discovery of a germline gain-of-function mutation in CARD11 illuminates how antigen receptor signaling is regulated differently in B and T cells, even though the proximal signaling machinery is nearly identical. This surprising difference has not been revealed by somatic CARD11 mutations in diffuse large cell B cell lymphoma, in which only B cells harbor the mutation and can potentially explain the preponderance of B cell rather than T-cell lymphomas associated with activating mutations in this gene. Our molecular analysis of this autosomal dominant lymphoproliferative disorder, which may represent a novel precursor state for B cell malignancies like B-chronic lymphocytic leukemia, reveals how selective dysregulation of NF-kappaB via CARD11 may predispose to selective proliferation and differentiation arrest in B cells, but defective proliferation and function of T cells. By re-examining the molecular basis of a rare genetic disorder first reported for decades ago, our discovery may open new avenues to treat this lymphoproliferative disease and prevent development of lymphoma by agents that can block NF-kB.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Zip Code
Kanellopoulou, Chryssa; Gilpatrick, Timothy; Kilaru, Gokhul et al. (2015) Reprogramming of Polycomb-Mediated Gene Silencing in Embryonic Stem Cells by the miR-290 Family and the Methyltransferase Ash1l. Stem Cell Reports 5:971-8
Chaigne-Delalande, Benjamin; Li, Feng-Yen; O'Connor, Geraldine M et al. (2013) Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D. Science 341:186-91
Lo, Bernice; Ramaswamy, Madhu; Davis, Joie et al. (2013) A rapid ex vivo clinical diagnostic assay for fas receptor-induced T lymphocyte apoptosis. J Clin Immunol 33:479-88
Pandiyan, Pushpa; Lenardo, Michael (2012) Comment on ""Cutting edge: regulatory T cells do not mediate suppression via programmed cell death pathways"". J Immunol 188:5203-4; author reply 5204-5
Snow, Andrew L; Xiao, Wenming; Stinson, Jeffrey R et al. (2012) Congenital B cell lymphocytosis explained by novel germline CARD11 mutations. J Exp Med 209:2247-61
Pandiyan, Pushpa; Yang, Xiang-Ping; Saravanamuthu, Senthil S et al. (2012) The role of IL-15 in activating STAT5 and fine-tuning IL-17A production in CD4 T lymphocytes. J Immunol 189:4237-46
Liu, Zhihua; Lenardo, Michael J (2012) The role of LRRK2 in inflammatory bowel disease. Cell Res 22:1092-4
Wan, Fengyi; Weaver, Amanda; Gao, Xiaofei et al. (2011) IKKβ phosphorylation regulates RPS3 nuclear translocation and NF-κB function during infection with Escherichia coli strain O157:H7. Nat Immunol 12:335-43
Wan, Fengyi; Lenardo, Michael J (2010) The nuclear signaling of NF-kappaB: current knowledge, new insights, and future perspectives. Cell Res 20:24-33
Bidere, Nicolas; Ngo, Vu N; Lee, Jeansun et al. (2009) Casein kinase 1alpha governs antigen-receptor-induced NF-kappaB activation and human lymphoma cell survival. Nature 458:92-6

Showing the most recent 10 out of 11 publications