During the immune response, naïve T cells are activated and undergo clonal expansion to yield several types of CD4+ effector T cells. T follicular helper (TFH) cells are a subset of CD4+ T cells that are required to support B cells to generate antibody in lymphoid structures known as germinal centers (GCs). In contrast, follicular regulatory T (TFR) cells antagonize TFH cells to inhibit antibody-based (humoral) immunity. On the surface of both TFH and TFR cells is the receptor PD-1 (programmed death 1), which inhibits T cell proliferation; however, there are conflicting reports of the role of PD-1 in humoral immunity. Using in vitro cell sorting and in vivo adoptive transfer methods, Sage et al. found that TFR cells potently suppressed the humoral immune response and that PD-1 inhibited the activation and function of TFR cells but not of TFH cells. Wild-type and PD-1–deficient mice were immunized with myelin oligodendrocyte glycoprotein (MOG) to induce the humoral immune response. TFR and TFH cells were separately isolated from lymph nodes by cell sorting first for common and then for TFR-specific surface markers. Genetic deletion of the costimulatory proteins CD28 or ICOS, which (like PD-1) are present on the surface of both cell types, reduced the numbers of these cells in the blood and lymph nodes of immunized mice. Whereas TFH cell numbers were unchanged by genetic deletion of PD-1 or either of its ligands, PD-L1 and PD-L2, TFR cells isolated from mice deficient in PD-1 or in PD-L1 (but not in PD-L2) were increased both in absolute numbers and as a proportion of total CD4+ T cells. TFR cells from these mice also had decreased abundance of the proliferation marker Ki67, indicating that the increased proportion of these cells was a result of increased differentiation rather than proliferation. Analysis of lymph node sections showed that PD-1–deficient TFR cells migrated into B cell–rich GCs as effectively as did wild-type TFR cells. In a coculture system containing TFR cells, TFH cells, and B cells from MOG-treated mice, when PD-1–deficient TFR cells were used instead of wild-type TFR cells there was enhanced suppression of immunoglobulin G (IgG) antibody production by the B cells. In vivo adoptive transfer studies, in which there was cotransfer of TFR and TFH cells isolated from the blood of immunized wild-type mice into a mouse strain lacking both cell types, showed more effective inhibition of IgG production compared with transfer of TFH cells alone; TFR cells from PD-1–deficient mice produced even stronger inhibition of IgG production. Together, these data suggest that PD-1, through its interaction with PD-L1, promotes the humoral immune response by inhibiting the differentiation and function of suppressive TFR cells.
P. T. Sage, L. M. Francisco, C. V. Carman, A. H. Sharpe, The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat. Immunol. 14, 152–161 (2013). [PubMed]