IL-21–producing effector Tfh cells promote B cell alloimmunity in lymph nodes and kidney allografts

Abstract

Follicular helper T (Tfh) cells have been implicated in controlling rejection after allogeneic kidney transplantation, but the precise subsets, origins, and functions of Tfh cells in this process have not been fully characterized. Here we show that a subset of effector Tfh cells marked by previous IL-21 production is potently induced during allogeneic kidney transplantation and is inhibited by immunosuppressive agents. Single-cell RNA-Seq revealed that these lymph node (LN) effector Tfh cells have transcriptional and clonal overlap with IL-21–producing kidney-infiltrating Tfh cells, implicating common origins and developmental trajectories. To investigate the precise functions of IL-21–producing effector Tfh cells in LNs and allografts, we used a mouse model to selectively eliminate these cells and assessed allogeneic B cell clonal dynamics using a single B cell culture system. We found that IL-21–producing effector Tfh cells were essential for transplant rejection by regulating donor-specific germinal center B cell clonal dynamics both systemically in the draining LN and locally within kidney grafts. Thus, IL-21–producing effector Tfh cells have multifaceted roles in Ab-mediated rejection after kidney transplantation by promoting B cell alloimmunity.

T follicular helper cells expansion in transplant recipients correlates with graft infiltration and adverse outcomes

“…However, the high incidence of chronic, antibody-mediated rejection in the long term is evidence that at some point during the host versus graft response, sufficient T cell priming occurs to trigger the generation of Tfh in a manner similar to vaccination. Recent data showing that alloreactive Tfh cells are primed in allograft-draining nodes suggest that the expansion of Tfh cells in the blood may only represent a proportion of this immune process ( 47 ).…”

Id1 expression in CD4 T cells promotes differentiation and function of follicular helper T cells and upregulation of related functional molecules

“…The assistance of TFH cells to B cells in T-dependent immune responses is indispensable, occurring following their activation and migration from the T-cell zone to the B-cell follicle [47], and subsequently to the GC [48]. During these processes, they secrete IL-21 [49], which binds to IL-21R on GC B cells, collaborating with engagement of B-cell antigen receptor and CD40, to promote the development and maturation of GCs [50,51]. We systematically investigated the changes in the development and function of GC B cells when all E proteins were inhibited.…”

Cytokines in Follicular Helper T Cell Biology in Physiologic and Pathologic Conditions

“…The suppression of the Pax3-Id3 pathway by IL-21 exacerbates the development of Sjögren’s syndrome by promoting the activity of Tfh cells, leading to heightened severity of disease symptoms ( 80 ). In the context of transplantation, IL-21-producing effector Tfh cells have been shown to drive B cell alloimmunity in lymph nodes and kidney allografts, suggesting a mechanism for transplant rejection ( 81 ). Furthermore, the role of IL-21 in neurodegenerative diseases has been identified, impacting neuro-immune communication between peripheral systems and the brain, which affects Alzheimer's disease neuropathology and may influence the progression and severity of the disease ( 82 ).…”