Transcriptionally Distinct B Cells Infiltrate Allografts After Kidney Transplantation

Abstract

Background. Following allogeneic kidney transplantation, a substantial proportion of graft loss is attributed to the formation of donor-specific antibodies and antibody-mediated rejection. B cells infiltrate kidney grafts during antibody-mediated rejection; however, the origins, repertoires, and functions of these intrarenal B cells remain elusive. Methods. Here, we use murine allogeneic kidney transplant models to study the origins, transcriptional programming and B cell receptor repertoire of intragraft B cells, and in vitro stimulation assays to evaluate the ability of intragraft B cells to promote CD4+ T cell expansion. Results. B cells infiltrate kidney grafts in settings of allogeneic, but not syngeneic, transplantation. Intragraft B cells have characteristics of activation but are transcriptionally distinct from germinal center B cells and resemble innatelike B cells. B cell receptor sequencing demonstrates that the majority of intragraft B cells do not originate from lymph node germinal center B cells and are largely germline. Class-switched intragraft B cells are rare but can be donor-specific and produce IgG capable of binding to the kidney allograft. Lastly, intrarenal B cells are capable of stimulating naive T cells but have an altered ability to promote T follicular helper cell expansion. Conclusions. Together, these data demonstrate that intrarenal B cells during transplant rejection are transcriptionally distinct from lymph node B cells.

Posttransplant Tertiary Lymphoid Organs

“… 67 Evidence that B-cell maturation occurs in PT-TLOs is apparent from the minimal overlap of B-cell alloantibody repertoires in human kidney grafts and peripheral blood 38 and the fact that B-cell clones in TLOs of rejecting human kidneys exhibit somatic mutations and differ from those in peripheral blood, 67 consistent with similar earlier studies of TLOs in transgenic models 41 , 64 and autoimmunity. 65 , 66 Nevertheless, the absence of defined dark and light zones typical of SLOs, the generation of autoantibodies, 1 and an apparent defect in the ability to expand Tfh cells in rejecting kidney lymphoid infiltrates 68 suggest that, although events typical of SLO GCs occur in TLOs, some differences exist.…”

Opportunities for High-plex Spatial Transcriptomics in Solid Organ Transplantation

“…54 In-depth analysis of histological features surrounding rejection would define the underlying immune–endothelial–epithelial–stromal interactions that contribute to damage, for example identifying how B-cell infiltrates or innate-like B cells may be retained, activated, or expanded in the cardiac and renal allografts. 55-57 Understanding these cellular interactions could lend insight into the development and nature of subclinical and borderline rejection episodes, of specific acute and chronic histological features, and of the contributions of donor and recipient immune cells to injury. 58-60…”

“…54 In-depth analysis of histological features surrounding rejection would define the underlying immune-endothelial-epithelial-stromal interactions that contribute to damage, for example identifying how B-cell infiltrates or innate-like B cells may be retained, activated, or expanded in the cardiac and renal allografts. [55][56][57] Understanding these cellular interactions could lend insight into the development and nature of subclinical and borderline rejection episodes, of specific acute and chronic histological features, and of the contributions of donor and recipient immune cells to injury. [58][59][60] In parallel to rejection, the high-resolution spatial analysis of tolerance and operational tolerance may reveal novel pathways to exploit therapeutically, for example, of regulatory lymphoid structures that can promote kidney allograft tolerance 61 or bronchus-associated lymphoid tissues from tolerant lung grafts that can promote peripheral tolerance.…”

Marginal Zone B Cells Are Necessary for the Formation of Anti-donor IgG After Allogeneic Sensitization

“…[16][17][18] Recent studies found that infiltrating B-cell populations in rejecting hearts and kidneys are responsive to innate stimuli and have self-reactivity. 6,7,19,20 In this study, we sought to understand the differentiation of B cells after exposure to allogeneic antigen by tracking antigen-specific B cells after sensitization. We found that MZ B cells are critical for the formation of GC B cells and anti-donor IgG and thus represent an enriched reservoir of alloreactive B cells.…”