Blockade of B7-H1 (Programmed Death Ligand 1) Enhances Humoral Immunity by Positively Regulating the Generation of T Follicular Helper Cells

Abstract

T follicular helper (TFH) cells are critical initiators in the development of T cell-dependent humoral immunity and the generation of protective immunity. We demonstrate that TFH cell accumulation and Ab production are negatively regulated by B7-H1 (programmed death ligand 1) in response to both helminth infection and active immunization. Following immunization of B7-H1−/− mice with keyhole limpet hemocyanin or helminth Ags, there is a profound increase in induction of TFH cells as a result of increased cell cycling and decreased apoptosis relative to wild-type mice. The increase in TFH cells in the absence of B7-H1 was associated with significant elevations in Ag-specific Ig response. Cotransfer experiments in vivo demonstrated that B7-H1 expression on B cells was required for negatively regulating TFH cell expansion and production of Ag-specific Ig. Treatment of immunized wild-type mice with anti–B7-H1 or anti-programmed death 1 mAbs, but not anti–B7-DC, led to a significant expansion of the TFH cell population and an enhanced Ag-specific Ig response. Our results demonstrate that the coinhibitory B7-H1/programmed death 1 pathway can limit the expansion of TFH cells and constrain Ag-specific Ig responses. This finding has direct implications for investigations examining the feasibility of therapeutically manipulating this pathway and reveals new insights into the regulation of the humoral immune response.

Identification and Characterization of MEDI4736, an Antagonistic Anti–PD-L1 Monoclonal Antibody

“…Splenocytes taken from mice treated in this way demonstrated increased IFNg release during in vitro culture with KLH, relative to those taken from mice treated with an isotype control antibody, which confirmed the potential of 10F.9G2 to enhance an on-going immune response. This result is consistent with other published studies looking at the effect of the PD-1/PD-L1 axis on response to foreign antigens (38,39), and supported the role of PD-L1 as a repressor of T-cell responses.…”

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

“…Thus, it is possible that both Tfh and extrafollicular helper T cells are involved in the development of hyper-IgG. PD-1 is a well-known marker for CD8 1 T-cell exhaustion [34] and recently the blockade of PD-1 has been reported to enhance Ab production in response to helminth infection [35]. However, PD-1 was also found to be involved in GC B-cell survival and formation of long-lived plasma cells [12].…”

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

“…Tfh cell regulation within the GC is mediated in part by inhibitory receptors, negative feedback loops, and the availability of antigen and growth factors, and it is also regulated by specialized populations of regulatory cells. The inhibitory receptor PD‐1 is expressed at high levels on Tfh cells, and engagement of PD‐1 by PD‐L1 on B cells prevents Tfh cell proliferation following antigen recognition on B cells 109, 220, 221. In addition to B cells, antigen‐specific plasma cells can also present antigen to Tfh cells.…”