The elucidation of the mechanism by which
Regulatory T-cells control vaccination responses-CTLA-4 controls antibody productionProfessor Shimon Sakaguchi of Osaka University IFReC has found that Regulatory T-cells(Tregs) use the immunoregulatory molecule CTLA-4 to suppress T-follicular helper cells, a T-cell
subset that is critical to antibody production. This finding is important to help us control antibody
production to develop better vaccines and new treatments for antibody driven autoimmunity.

Introduction
Following infection or vaccination the immune system
must produce antibodys that attack pathogens such as
viruses and bacteria in order to protect the host.
However overactivation of the immune system may leadto the production of antibodies that attack our own
bodies and cause autoimmune diseases such as systemic
lupus erythematosus (SLE) and Rheumatoid arthritis(RA). Tregs are a specialized set of T-cells that suppress
the activation of other cells and loss of Treg function that
leads to fatal autoimmunity. Thus Tregs must walk atightrope in which they allow antibody production topathogens and following vaccination but prevent theproduction of autoimmune antibodies targeting the host.
However the role of Tregs in the control of antibody
producing B-cells was only partially understood. We set
out to determine the role of Tregs in control of antibody
production following vaccination and the mechnism bywhich they achieve their effect.

Tregs suppress antibody production
via CTLA-4

The key points are:Depletion of Treg cells, and their subset T-follicular regs, leads to enhanced numbers ofT-follicular helper cells (Tfh), a T-cell subtype that specializes in delivering help to B-cells andenhances their conversion to antibody producing plasma B-cells. However importantly, only
short term depletion of Tregs enhanced antigen specific cells while longer term depletion ofTregs increased autoimmune antibody production, demonstrating the complex role of Tregs inantibody production.
Depletion of Tregs also enhances memory B-cell production and antibody production
following later vaccination without further Treg depletion suggesting that a single depletion ofTregs during primary vaccination will lead to stability enhanced immunity for long periods oftime.

The mechanism by which Tregs control Tfh numbers is by depletion of stimulatory
molecules from the surface of antigen presenting cells (including B-cells) via the co-inhibitory
molecule CTLA-4. As a result blocking of CTLA-4 enhanced antibody responses to vaccination.
While mice with Treg targeted depletion of of CTLA-4 develop spontaneous formation of large
numbers of Tfh and germinal center B-cells, which are the source of plasma and memory
B-cells.
These results are important as they will allow us to develop new ways to either decrease Treg
function to enhance vaccine responses or boost Treg function to prevent antibody driven
autoimmunity.

KEYWORDS
Regulatory T cell (Treg), CTLA-4, T-follicular helper cells (Tfh)
ARTICLE & JOURNAL
James Badger Wing, Wataru Ise, Tomohiro Kurosaki, and Shimon Sakaguchi. Regulatory TCells Control Antigen-Specific Expansion of Tfh Cell Number and Humoral Immune Responses
via the Coreceptor CTLA-4. Immunity (2014).

Figure 1A) Tfh cell (BCL6+CXCR5+) formation in wildtype (WT), Treg depleted (DEREG) or Treg specific
CTLA4 deficient mice.
B) Enhanced B-cell germinal center, plasma cell and memory B-cell formation in Treg depletedDEREG mice.