Background/Purpose: CD27 is a member of the TNF superfamily of receptors that is expressed on a majority of natural killer (NK) cells, T cells, memory B cells and antibody-secreting plasma cells in humans.  CD70 is the only known ligand for CD27 and is transiently expressed on activated dendritic cells, B cells and T cells.  Much of our understanding of the immunological role of CD27 comes from studies with mouse models, which suggest that CD27 is a key regulator of NK cell, T cell and B cell responses. Here, we used an in-house generated neutralizing, antagonistic antibody to evaluate the role of CD27 in regulating human and primate immune responses using in vitro and in vivo models.

Methods: To examine the role of CD27 in immune cell biology, we generated a neutralizing, antagonistic and non-depleting human anti-human CD27 antibody.  To assess the contribution of CD27 signaling to human immune responses in vitro, we examined the effects of CD27 blockade on Ig-production by B cells, proliferation of naive CD4⁺ T cells and cytokine production by healthy volunteer PBMCs in vitro.  To understand the role of CD27 on immune responses in vivo, we examined the effects of CD27 blockade on T and B cell responses in a cynomolgus monkey Delayed Type Hypersensitivity (DTH) model.  To further explore the contribution of CD27 to human T cell responses in vivo, we examined the effects of CD27 blockade on human T cell engraftment in the NSG (NOD/SCID IL-2Rγ^-/-) human CD45⁺ peripheral blood cell → mouse GVH model.  

Results: We found that neutralizing the CD27 pathway inhibited CD70-induced Ig-secretion by activated human B cells, whereas blockade of CD27 in an autologous T cell:B cell co-culture model did not impact Ig-secretion in vitro (despite expression of CD70 on cells in this system).  Treatment with an anti-CD27 antibody dose-dependently attenuated CD70-mediated induced proliferation of primary human CD4⁺ T cells and decreased the production of pro-inflammatory cytokines by healthy control PBMCs in vitro.  Treatment with an anti-CD27 antibody reduced human CD45⁺ CD4⁺ and CD8⁺ cell numbers in the spleen and peripheral blood of host mice in the human cell → NSG mouse GVH model.  Blockade of CD27 reduced T cell infiltration into the challenge site in response to a neo-antigen, but did not impact antigen-specific antibody titers in a cynomolgus monkey DTH model.

Conclusion: These data demonstrate that CD27 can promote Ig-production by human B cells, but may play a redundant role in some types of B cell responses.  In contrast, CD27 appears to play a critical role in the generation of both CD4⁺ and CD8⁺ T cell responses.  These data suggest that the CD27 pathway modulates the activity of multiple human immune cell types, and that blockade of the CD27 pathway may present a novel therapeutic strategy for the treatment of immune mediated diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cd27-is-a-key-regulator-of-t-cell-responses/