Regulatory T Cells Control Antigen-Specific Expansion of Tfh Cell Number and Humoral Immune Responses via the Coreceptor CTLA-4

• Short-term Treg cell depletion enhances primary and secondary antibody production
• Depletion of Treg cells can either enhance or inhibit antigen-specific Tfh cell formation
• Deletion or blockade of Treg cell CTLA-4 enhances Tfh cell formation, IL-4 production, and IgE
• Tfr cells possess similar in vitro suppressive CTLA-4 function to Treg cells

SummaryCD4+Foxp3-expressing Treg cells, which constitutively express the inhibitory coreceptor CTLA-4, are indispensable for immune homeostasis. We determined the roles of Treg cells and T follicular regulatory (Tfr) cells in the control of humoral immune responses. Depletion of Treg cells, blocking of CTLA-4 or a Treg cell specific reduction in CTLA-4 expression, resulted in an increase in the formation of antigen-specific Tfh cells, germinal center (GC), and plasma and memory B cells after vaccination. In the absence of Treg cell-expressed CTLA-4, large numbers of Tfr cells were present but were unable to restrain Tfh cell and GC formation. Temporary Treg cell depletion during primary immunization was sufficient to enhance secondary immune responses. Treg cells directly inhibited, via CTLA-4, B cell expression of CD80 and CD86, which was essential for Tfh cell formation. Thus, Treg and Tfr cells control Tfh cell and germinal center development, via CTLA-4-dependent regulation of CD80 and CD86 expression.