T Follicular Helper Cells As a New Target for Immunosuppressive Therapies

Abstract

Over the past decade, antibody-mediated (humoral) rejection has been recognized as a common cause of graft dysfunction after organ transplantation and an important determinant for graft loss. In humoral alloimmunity, T follicular helper (Tfh) cells play a crucial role, because they help naïve B cells to differentiate into memory B cells and alloantibody-producing plasma cells within germinal centers. In this way, they contribute to the induction of donor-specific antibodies, which are responsible for the humoral immune response to the allograft. In this article, we provide an overview of the current knowledge on the effects of immunosuppressive therapies on Tfh cell development and function, and discuss possible new approaches to influence the activity of Tfh cells. In addition, we discuss the potential use of Tfh cells as a pharmacodynamic biomarker to improve alloimmune-risk stratification and tailoring of immunosuppression to individualize therapy after transplantation.

Keywords: T follicular helper cells; allograft rejection; costimulation; cytokines; donor-specific antibodies; humoral immunity; immunosuppression; transplantation.

Figure 1

T follicular helper (Tfh) cell differentiation, activation, and crosstalk. Schematic overview of molecules involved in the differentiation of Tfh cells, the activation of Tfh cells by dendritic cells (DCs) and B cells, and the crosstalk of Tfh cells with DCs and B cells.

Figure 2

Possible effect of tacrolimus (Tac) and basiliximab on T follicular helper (Tfh) cell differentiation and activation. (A) An activated T cell is depicted in the upper panel. (B) After addition of Tac, calcineurin (CaN) is blocked, and dephosphorylation of cytoplasmic nuclear factor in activated T cells (NFAT) is inhibited resulting in lower levels of IL-2 transcription. IL-2 promotes transcription of B lymphocyte-induced maturation protein-1 (Blimp-1), a co-repressor of B cell lymphoma 6 (Bcl-6). In the absence of IL-2, lower transcription of Blimp-1 leads to increased expression of BCL6 and thus may enhance Tfh cell numbers. Basiliximab may promote the same effect of enhancing Tfh cell numbers via blocking the IL-2R.

Figure 3

T follicular helper (Tfh)-targeted immunotherapy. Blockage of the Tfh activation and function is established via several routes. An overview of these Tfh-targeted immunotherapies is summarized in this figure with (1) belatacept/abatacept, blocking costimulation of CD28/cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and CD80/CD86, (2) anti-inducible T cell costimulatory molecule (ICOS), (3) anti-CD40, (4) anti-OX40, (5) anti toll-like receptor 7 (TLR7) or toll-like receptor 9 (TLR9), (6) anti-IL-21R, (7) anti-IL-6R, and (8) anti-C–X–C chemokine ligand 13 (CXCL13) and anti-CXCL10.