Transplantation tolerance modifies donor-specific B cell fate to suppress de novo alloreactive B cells
Stella H.W. Khiew, … , Maria-Luisa Alegre, Anita S. Chong
Stella H.W. Khiew, … , Maria-Luisa Alegre, Anita S. Chong
Published May 26, 2020
Citation Information: J Clin Invest. 2020;130(7):3453-3466. https://doi.org/10.1172/JCI132814.
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Transplantation tolerance modifies donor-specific B cell fate to suppress de novo alloreactive B cells

Abstract

The absence of alloantibodies is a feature of transplantation tolerance. Although the lack of T cell help has been evoked to explain this absence, herein we provide evidence for B cell–intrinsic tolerance mechanisms. Using a murine model of heart tolerance, we showed that alloreactive B cells were not deleted but rapidly lost their ability to differentiate into germinal center B cells and secrete donor-specific antibodies. We inferred that tolerant alloreactive B cells retained their ability to sense alloantigen because they continued to drive T cell maturation into CXCR5+PD-1+ T follicular helper cells. Unexpectedly, dysfunctional alloreactive B cells acquired the ability to inhibit antibody production by new naive B cells in an antigen-specific manner. Thus, tolerant alloreactive B cells contribute to transplantation tolerance by foregoing germinal center responses while retaining their ability to function as antigen-presenting cells and by actively suppressing de novo alloreactive B cell responses.

Authors

Stella H.W. Khiew, Dharmendra Jain, Jianjun Chen, Jinghui Yang, Dengping Yin, James S. Young, Alexander Dent, Roger Sciammas, Maria-Luisa Alegre, Anita S. Chong

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Figure 1

Alloreactive B cells are not deleted in tolerant recipients.

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Alloreactive B cells are not deleted in tolerant recipients. (A) B/c (H-...
(A) B/c (H-2d) or B/c.2W-OVA heart allografts were transplanted into C57BL/6 (B6, H-2b) recipients that were untreated (acutely rejecting, AR) or treated with anti-CD154 (αCD154) on day 0 (D0), D7, and D14 plus DSCs (D0) to induce allograft tolerance. (B) Survival of allograft in AR or tolerant (Tol) mice. n = 10–40/group; P < 0.0001 by log-rank test. (C) Donor-specific antibodies–IgG (DSA-IgG) from Tol mice on postoperative day (POD) 0, 14, 45, 60, and 90 after heart transplant (HTx) and AR D14. n = 9–12/group. Representative flow plots of H-2Kd–binding B cells in naive B6 mice were identified using (D) double-positive (DP) donor MHC class I (Kd) tetramer conjugated to PE or APhC fluorochromes, and (E) decoy Kb (recipient MHC) tetramer conjugated to PE and AF647 in combination with Kd-PE tetramers. (F–H) Splenocytes and inguinal, axillary, and branchial lymph node cells were pooled and the total number of (F) Kd, (G) Ld, and (H) I-Ed tetramer–binding B cells from naive, Tol, or naive MD4 (anti-HEL BCR-Tg) mice were analyzed. n = 4–12/group. mse, mouse. (I–K) Normalized mean fluorescence intensity (MFI) of (I) Kd, (J) Ld, and (K) I-Ed tetramer–specific B cells from naive and Tol mice. n = 6–10/group. MFIs were normalized to DP or decoy tetramer–binding B cells of naive B6 mice. Data were pooled from 2 or more independent experiments and are presented as the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 2-way ANOVA with Tukey’s post hoc test for multiple comparisons (F–H) or 1-way ANOVA with Bonferroni’s post hoc test (C).