Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions

Abstract

Foxp3+ regulatory T (Treg) cells suppress different types of immune responses to help maintain homeostasis in the body. How Treg cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of Treg cells expressing CXCR5 and Bcl6, and localized in the germinal centers in mouse as well as human. The expression of CXCR5 on Treg cells depends on Bcl6. These CXCR5+Bcl6+ Treg cells are absent in thymus but can be de novo generated from CXCR5-Foxp3+ natural Treg precursors. Lack of CXCR5+ Treg cells leads to greater germinal center reactions. These results unveil a Bcl6-CXCR5 axis in Treg cells that undermines the development of follicular regulatory T (Tfr) cells that function to inhibit the germinal center reaction.

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…By regulating initial CD4 + T‐cell activation and differentiation FoxP3 +  CD4 + Treg cells can reduce the initial generation of Tfh cells, although they may also enhance CD4 + T‐cell differentiation into Tfh cells by sequestering IL‐2 234. However, regulatory CD4 + T cells are also found within GCs,235 and recent studies have shown that a subset of CXCR5 +  FoxP3 +  CD4 + Treg cells, termed T follicular regulatory (Tfr) cells, are generated as immune responses are induced and localize to the GC to control the GC response 236, 237, 238. In mice, Tfr cells have been shown to reduce antibody production and the number of GC B cells, antigen‐specific B cells, and plasma cells 236, 237, 238, 239, 240, 241.…”

“…However, regulatory CD4 + T cells are also found within GCs,235 and recent studies have shown that a subset of CXCR5 +  FoxP3 +  CD4 + Treg cells, termed T follicular regulatory (Tfr) cells, are generated as immune responses are induced and localize to the GC to control the GC response 236, 237, 238. In mice, Tfr cells have been shown to reduce antibody production and the number of GC B cells, antigen‐specific B cells, and plasma cells 236, 237, 238, 239, 240, 241. Multiple stages of the B‐cell differentiation process are inhibited, from initial B‐cell activation to the generation of class‐switched B cells and plasma cells.…”

“…Following their initial generation, Tfr cells may either leave the LN and enter the circulation to become memory Tfr cells242 or migrate into the B‐cell follicles where they interact with B cells and undergo full differentiation into effector Tfr cells 239. Tfr cell differentiation following interaction with both DCs and B cells requires co‐stimulation though CD28 and ICOS, and SAP‐dependent stimulation by B cells 236, 237, 239, 247, 248. CTLA‐4 expression on Tfr cells inhibits their differentiation and maintenance via interaction with CD80/86 on DCs and B cells240, 249; and PD‐1 ligation inhibits both Tfr cell differentiation and their subsequent function 239…”

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

“…T FH cell-like features can also be exhibited by other subsets of T cells, including regulatory T (T reg ) and invariant natural killer T (iNKT) cells. [24][25][26][27] In particular, recent studies have described a population of follicular T regulatory (T FR ) cells that share the phenotypic characteristics with T FH and T reg cells. Like classic T FH cells, the so-called T FR cells express high levels of CXCR5 and PD-1, and require Bcl6, SAP and CD28 for their development, but they express Foxp3 and can inhibit the GC reactions, similar to T reg cells.…”

“…T FR cells are considered to be produced de novo from the progenitors of CXCR5 2 Foxp3 natural T reg cells. [25][26][27] Interestingly, the expression of T FH cell-like phenotype is not just confined to conventional T cells. Chang et al 24 recently identified a subset of iNKT, iNKT FH , cells that share phenotypic, functional and ontological characteristics of T FH cells.…”