TY - JOUR
T1 - Pathway-specific defects in t, b, and nk cells and age-dependent development of high ige in mice heterozygous for a cadins-associated dominant negative card11 allele
AU - Hutcherson, Shelby M.
AU - Bedsaul, Jacquelyn R.
AU - Pomerantz, Joel L.
N1 - Funding Information:
This work was supported by National Institutes of Health Grant RO1AI148143 and funds from The Johns Hopkins University Institute for Cell Engineering. S.M.H. was supported by National Institutes of Health Grants T32GM007445 and T32CA009110. J.R.B. was supported by National Institutes of Health Grant T32AI007247.
Publisher Copyright:
© 2021 American Association of Immunologists. All rights reserved.
PY - 2021/8/15
Y1 - 2021/8/15
N2 - CARD11 is a multidomain scaffold protein required for normal activation of NF-kB, JNK, and mTOR during Ag receptor signaling. Germline CARD11 mutations cause at least three types of primary immunodeficiency including CARD11 deficiency, B cell expansion with NF-kB and T cell anergy (BENTA), and CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS). CADINS is uniquely caused by heterozygous loss-of-function CARD11 alleles that act as dominant negatives. CADINS patients present with frequent respiratory and skin infections, asthma, allergies, and atopic dermatitis. However, precisely how a heterozygous dominant negative CARD11 allele leads to the development of this CADINS-specific cluster of symptoms remains poorly understood. To address this, we generated mice expressing the CARD11 R30W allele originally identified in patients. We find that CARD11R30W/+ mice exhibit impaired signaling downstream of CARD11 that leads to defects in T, B, and NK cell function and immunodeficiency. CARD11R30W/+ mice develop elevated serum IgE levels with 50% penetrance that becomes more pronounced with age, but do not develop spontaneous atopic dermatitis. CARD11R30W/+ mice display reduced regulatory T cell numbers, but not the Th2 expansion observed in other mice with diminished CARD11 activity. Interestingly, the presence of mixed CARD11 oligomers in CARD11R30W/+ mice causes more severe signaling defects in T cells than in B cells, and specifically impacts IFN-g production by NK cells, but not NK cell cytotoxicity. Our findings help explain the high susceptibility of CADINS patients to infection and suggest that the development of high serum IgE is not sufficient to induce overt atopic symptoms.
AB - CARD11 is a multidomain scaffold protein required for normal activation of NF-kB, JNK, and mTOR during Ag receptor signaling. Germline CARD11 mutations cause at least three types of primary immunodeficiency including CARD11 deficiency, B cell expansion with NF-kB and T cell anergy (BENTA), and CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS). CADINS is uniquely caused by heterozygous loss-of-function CARD11 alleles that act as dominant negatives. CADINS patients present with frequent respiratory and skin infections, asthma, allergies, and atopic dermatitis. However, precisely how a heterozygous dominant negative CARD11 allele leads to the development of this CADINS-specific cluster of symptoms remains poorly understood. To address this, we generated mice expressing the CARD11 R30W allele originally identified in patients. We find that CARD11R30W/+ mice exhibit impaired signaling downstream of CARD11 that leads to defects in T, B, and NK cell function and immunodeficiency. CARD11R30W/+ mice develop elevated serum IgE levels with 50% penetrance that becomes more pronounced with age, but do not develop spontaneous atopic dermatitis. CARD11R30W/+ mice display reduced regulatory T cell numbers, but not the Th2 expansion observed in other mice with diminished CARD11 activity. Interestingly, the presence of mixed CARD11 oligomers in CARD11R30W/+ mice causes more severe signaling defects in T cells than in B cells, and specifically impacts IFN-g production by NK cells, but not NK cell cytotoxicity. Our findings help explain the high susceptibility of CADINS patients to infection and suggest that the development of high serum IgE is not sufficient to induce overt atopic symptoms.
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U2 - 10.4049/jimmunol.2001233
DO - 10.4049/jimmunol.2001233
M3 - Article
C2 - 34341167
AN - SCOPUS:85113378717
SN - 0022-1767
VL - 207
SP - 1150
EP - 1164
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -