1 5 2 VOLUME 14 NUMBER 2 FEBRUARY 2013 nature immunology

Abstract

A r t i c l e s Follicular helper T cells (T FH cells) are a subset of CD4 + T cells that are essential for helping cognate B cells form and maintain the germinal center (GC) reaction and for the development of humoral immune responses. These cells are universally defined by expression of the chemokine receptor CXCR5, which directs them to B cell follicles via gradients of the chemokine CXCL13 (ref. 1). T FH cells also express the transcription factor Bcl-6 and have high expression of the costimulatory receptor ICOS. Both Bcl-6 and ICOS are critical for the differentiation and maintenance of T FH cells 1−4 . In addition, T FH cells secrete large amounts of interleukin 21 (IL-21), which aids in the formation of GCs, isotype switching and the formation of plasma cells 5 . In humans and mice, functionally similar T FH cells can be found in secondary lymphoid organs. CXCR5 + T FH cells are also present in peripheral blood and are found in greater abundance in people with autoantibodies, including patients with systemic lupus erythematosus, myasthenia gravis or juvenile dermatomyositis. However, the function of circulating T FH cells has remained unclear T FH cells also have high expression of the inhibitory receptor PD-1 (CD279). Signaling through PD-1 attenuates signaling from the T cell antigen receptor (TCR) and inhibits the population expansion, cytokine production and cytolytic function of T cells. In addition, PD-1 promotes the development of induced regulatory T cells (T reg cells) from naive lymphocytes 10-14 . PD-1 has two ligands: PD-L1 (B7-H1) and PD-L2 (B7-DC). PD-L1 has wider expression than does PD-L2, but both PD-L1 and PD-L2 can be expressed on GC B cells and dendritic cells PD-1 also is found on the CD4 + CXCR5 + subset of cells called 'follicular regulatory T cells' (T FR cells), which express the transcription factors Foxp3, Bcl-6 and Blimp-1 and function to inhibit the GC response Here we found that PD-1-PD-L1 interactions inhibited the number of T FR cells, but not of T FH cells, in the lymph nodes. PD-1-deficient mice had more T FR cells in the lymph nodes than did wild-type mice. PD-1-deficient T FR cells in the lymph nodes had an enhanced ability to suppress both the activation of naive T cells and antibody production in vitro. In addition, we found that T FR cells were present in the peripheral blood of mice and that these circulating cells potently regulated humoral immune responses in vivo. Through the use of transfer approaches, we found that T FH cells in the blood promoted antibody production, whereas T FR cells in the blood strongly inhibited antibody production in vivo. We further found that the PD-1 pathway inhibited the function of T FR cells in the blood and that PD-1-deficient T FR cells in the blood had enhanced suppressive ability in vivo. Together our studies identify a previously unknown immunoregulatory role for the PD-1-PD-L1 pathway in limiting th