TACI deficiency enhances antibody avidity and clearance of an intestinal pathogen
Shoichiro Tsuji, … , Jeffrey L. Platt, Marilia Cascalho
Shoichiro Tsuji, … , Jeffrey L. Platt, Marilia Cascalho
Published October 1, 2014
Citation Information: J Clin Invest. 2014;124(11):4857-4866. https://doi.org/10.1172/JCI74428.
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Research Article Immunology

TACI deficiency enhances antibody avidity and clearance of an intestinal pathogen

Abstract

The transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) controls differentiation of long-lived plasma cells, and almost 10% of individuals with common variable immunodeficiency (CVID) express either the C104R or A181E variants of TACI. These variants impair TACI function, and TACI-deficient mice exhibit a CVID-like disease. However, 1%–2% of normal individuals harbor the C140R or A181E TACI variants and have no outward signs of CVID, and it is not clear why TACI deficiency in this group does not cause disease. Here, we determined that TACI-deficient mice have low baseline levels of Ig in the blood but retain the ability to mutate Ig-associated genes that encode antigen-specific antibodies. The antigen-specific antibodies in TACI-deficient mice were produced in bursts and had higher avidity than those of WT animals. Moreover, mice lacking TACI were able to clear Citrobacter rodentium, a model pathogen for severe human enteritis, more rapidly than did WT mice. These findings suggest that the high prevalence of TACI deficiency in humans might reflect enhanced host defense against enteritis, which is more severe in those with acquired or inherited immunodeficiencies.

Authors

Shoichiro Tsuji, Lucas Stein, Nobuhiko Kamada, Gabriel Nuñez, Richard Bram, Bruce A. Vallance, Ana E. Sousa, Jeffrey L. Platt, Marilia Cascalho

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Figure 4

Comparison of the phenotype and fraction of Tfh cells in spleens of immunized WT or TACI-deficient mice.

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Comparison of the phenotype and fraction of Tfh cells in spleens of immu...
(A) TACI expression by GC cells and Tfh cells. Tfh cells were identified as CD4+CXCR5+ and PD1+ by FACS (upper panel) and tested for expression of Bcl6 or Taci mRNA by qPCR (middle and lower panels, respectively). Tfh cells from TACI-deficient mice expressed as much Bcl6 as those from WT mice (middle panel). Taci expression by T cells was equivalent to that in GC B cells (lower panel). (B) Relative number of Tfh cells in spleens of WT and TACI-deficient mice before (Pre-I) and 5, 8, and 28 days after immunization with SRBCs. Frequencies of Tfh cells in C57BL/6 and Taci-KO mice were compared by 1-way ANOVA and Holm-Sidak multiple comparison tests. Pre-I, P = 0.0015; day 5, P = 0.0004; day 8, P < 0.0001; day 28, P > 0.9999 was nonsignificant. (C) Impact of TACI expression by B and T cells on the size of the Th cell population. Number of Th cells of donor (CD45.2+) or recipient origin (CD45.1+) was determined in chimeras reconstituted as shown in Figure 3 relative to chimeras reconstituted with WT-T and WT-QM B cells, 8 days after immunization with 100 μg NP conjugated with OVA. Increase in the number of CD4+ Th cells was secondary to B cell–intrinsic TACI deficiency. Comparisons by 1-way ANOVA and Holm-Sidak multiple comparison tests. ***P = 0.0001; **P = 0.0013.