Unconventional, adenosine-producing suppressor T cells induced by dendritic cells exposed to BPZE1 pertussis vaccine

Abstract

BPZE1 is a live attenuated pertussis vaccine that successfully completed a phase 1 safety trial. This article describes the induction of unconventional suppressor T cells-producing ADO by MDDCs exposed to BPZE1 (BPZE1-DC) through distinct ectoenzymatic pathways that limit the damaging effect of inflammation. BPZE1-DC induces CD4(+) and CD8(+) T lymphocytes to express 2 sets of ectoenzymes generating ADO: 1 set is part of the conventional CD39/CD73 pathway, which uses ATP as substrate, whereas the other is part of the CD38/CD203a/CD73 pathway and metabolizes NAD(+). The contribution of the ADO-generating ectoenzymes in the regulatory response was shown by: 1) selective inhibition of the enzymatic activities of CD39, CD73, and CD38; 2) the ability of suppressor T cells to convert exogenously added ATP and NAD(+) to ADO; and 3) a positive correlation between ectoenzyme expression, ADO levels, and suppression abilities. Thus, T lymphocytes activated by BPZE1-DC shift to a suppressor stage, through the expression of ectoenzyme networks, and are able to convert extracellular nucleotides into ADO, which may explain the potent anti-inflammatory properties of BPZE1 observed in several murine models.

Targeting CD73 in the tumor microenvironment with MEDI9447

“…Although a similar primary lymphocyte reaction system has been reported for studying the immunosuppressive effects adenosine in vitro , 27 our studies include a the full array of myeloid and lymphoid cells present in primary PBMC samples. The apparent potency of MEDI9447 in the MLR was less than that observed in those experiments demonstrating relief from AMP-mediated lymphocyte proliferation.…”

CD38, a Receptor with Multifunctional Activities: From Modulatory Functions on Regulatory Cell Subsets and Extracellular Vesicles, to a Target for Therapeutic Strategies

“…Such cells are able to produce ADO starting from ATP and NAD + . Experiments performed using specific inhibitors of CD38, CD39 and CD73 clearly demonstrated that both pathways are crucial for CD4 + /CD8 + regulatory T cell functions, which are strictly related to the resulting levels of ADO [21].…”

Microvesicles released from multiple myeloma cells are equipped with ectoenzymes belonging to canonical and non-canonical adenosinergic pathways and produce adenosine from ATP and NAD+

“…The last step is shared with the conventional pathway, and CD73 metabolizes AMP to ADO. 13,14 Ectoenzymes belonging to the alternative pathway in the BM niche are expressed by different cell populations, since CD38 is expressed at high levels by PC [which are CD73 ¡ /CD203a(PC-1) ¡ ], CD203a (PC-1) is expressed by MSC and OB, while CD73 is expressed by OB and OC. 9 The CD38/CD203a(PC-1)/CD73 pathway is operative to generate ADO in a discontinuous fashion, whereby all the enzymatic molecules are expressed on different cells present in a closed BM environment.…”