T Follicular Regulatory Cells and Antibody Responses in Transplantation

Abstract

De novo donor-specific antibody (DSA) formation is a major problem in transplantation, and associated with long-term graft decline and loss as well as sensitization, limiting future transplant options. Forming high-affinity, long-lived antibody responses involves a process called the germinal center (GC) reaction, and requires interaction between several cell types, including GC B cells, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. T follicular regulatory cells are an essential component of the GC reaction, limiting its size and reducing nonspecific or self-reactive responses.An imbalance between helper function and regulatory function can lead to excessive antibody production. High proportions of Tfh cells have been associated with DSA formation in transplantation; therefore, Tfr cells are likely to play an important role in limiting DSA production. Understanding the signals that govern Tfr cell development and the balance between helper and regulatory function within the GC is key to understanding how these cells might be manipulated to reduce the risk of DSA development.This review discusses the development and function of Tfr cells and their relevance to transplantation. In particular how current and future immunosuppressive strategies might allow us to skew the ratio between Tfr and Tfh cells to increase or decrease the risk of de novo DSA formation.

Figure 1. Dynamics of the germinal centre and development of Tfh and Tfr cells

A. Development of Tfh and GC B cells. Priming of naïve CD4 T cells occurs in the T cell zone by dendritic cells. Following this interaction, Tfh form a fate decision and can exit the SLO and enter the circulation as cTfh, or migrate towards the T-B border and undergo cognate interactions with B cells, allowing exchange of survival and proliferation signals. This induces Bcl6 in pre-Tfh, allowing further upregulation of CXCR5 and entry into the B cell follicle. B. Initiation of the GC and development of Tfr. After priming by pre-Tfh at the T-B border, B cells move into the follicle and begin to proliferate, forming a germinal centre that is supported by the Tfh that have upregulated CXCR5 and entered the follicle. Within 3-4 days a GC has been established and both cell types are proliferating, supported by follicular dendritic cells (FDCs). Tregs are similarly primed by DCs and can either exit the SLO and enter the circulation as cTfr or, following interactions with B cells at the T-B border, enter into the B cell follicle to become bona fide Tfr cells and regulate the GC response. C. Collapse of the GC response. By 7 days the GC response has reached its peak. High affinity B cells receive help to become long lived plasma or memory B cells and exit the SLO to enter the circulation, where the plasma cells will traffic to bone marrow niches. Tfr are present in the B cell follicle and begin to suppress the GC reaction, but it is not know if they exert effects on Tfh, GC B cells, the interactions between them, or a combination. By day 10 Tfh numbers are falling, Tfr numbers still rising, and the GC begins to collapse.