Low proportion of follicular regulatory T cell in renal transplant patients with chronic antibody-mediated rejection

Abstract

Follicular regulatory T (Tfr) cell can effectively regulate humoral immunity, but its function and mechanism in antibody-mediated rejection (AMR) after organ transplantation remains unclear. Here we detected follicular helper T (Tfh) cell subsets in 88 renal transplant patients with chronic renal allograft dysfunction (40 with AMR and 48 without AMR). The ratio of Tfr cells in renal graft tissues and peripheral blood of AMR patients significantly decreased, while the ratio of IL-21-producing Tfh cells (Tfh2 and Tfh17) significantly increased, compared to non-AMR patients. When tested in functional assays, Tfr cells from both AMR and non-AMR patients exerted equivalent inhibitory function. Tfr cell transplantation or CTLA-4 virus transfection could significantly inhibit IL-21 secretion from Tfh cells of these patients, further suppress the proliferation and differentiation of B cells. CTLA-4 blocking, IL-10 and TGF-β neutralization could partially weaken such inhibitory effect of Tfr cells. Besides, our study found that sirolimus reduced the ratio of Tfr cells, while cyclosporine and tacrolimus had no significant effect on Tfr cells. In a word, renal transplant patients with AMR have low proportion of Tfr cells but these cell exerted normal function.

T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments

“…15 In multiple sclerosis, myasthenia gravis, systemic lupus erythematosus, and rheumatoid arthritis, a decreased frequency of bTfr cells was observed. [155][156][157][158] However, a higher frequency of bTfr cells was found in patients with ankylosing spondylitis, systemic lupus erythematosus, and Sjögren's syndrome (SS). [159][160][161][162][163] Importantly, most of the literature describes studies where what is defined as Tfh cells contain both Tfh and CXCR5 + Tfr cells, likewise many other studies identify as Treg cells a mixture of conventional Treg cells together with Tfr cells.…”

Follicular regulatory T cells: a novel target for immunotherapy?

“…Although the emphasis of Tfr‐cell studies is mainly on AIDs, vaccine responses and other diseases including infections, cancers, allergies, chronic graft rejection/graft‐versus‐host disease (GVHD) and acute respiratory distress syndrome (ARDS) have also been under investigation (shown in Table ).…”

“…However, Tfr cells exhibit equivalent suppressive function between AMR and non‐AMR patients. An increase in the Tfr‐cell ratio inhibits the expression of IL‐21 in Tfh cells, the proliferation and differentiation of B cells, and IgG and IgA secretion of plasma cells . The miR‐17–92 cluster is proved to facilitate Tfh‐cell differentiation and impair Tfr/Tfh balance, thus accelerating the development of chronic GVHD in mice .…”

“…In renal transplant patients with chronic renal allograft dysfunction, frequencies of Tfr cells in peripheral blood and renal grafts from those with antibody-mediated rejection (AMR) are significantly decreased, while the frequency of IL-21-producing Tfh cells is increased, relative to those non-AMR patients. 94 However, Tfr cells exhibit equivalent suppressive function between AMR and non-AMR patients. An increase in the Tfr-cell ratio inhibits the expression of IL-21 in Tfh cells, the proliferation and differentiation of B cells, and IgG and IgA secretion of plasma cells.…”

“…An increase in the Tfr-cell ratio inhibits the expression of IL-21 in Tfh cells, the proliferation and differentiation of B cells, and IgG and IgA secretion of plasma cells. 94 The miR-17-92 cluster is proved to facilitate Tfhcell differentiation and impair Tfr/Tfh balance, thus accelerating the development of chronic GVHD in mice. 38 In addition, Tfr cells prompt lymphangiogenesis and Breg proliferation, exerting an atheroprotective effect in Apoe À/À mice transferred with Tfr cells.…”