The small-molecule BCL6-inhibitor 79-6 suppresses follicular T helper cell differentiation and plasma blast formation

R. Kraaijeveld, D.A. Hesselink, C.C. Baan

Wednesday 4 march 2020

14:50 - 15:00h at Joep Nicolas zaal

Parallel session: Parallel sessie IV – Basale abstracts

Background: In kidney transplantation, antibody mediated rejection is a major cause of graft loss amongst patients. The currently prescribed immunosuppressive treatments insufficiently control this humoral B cell mediated immune response. This humoral response is not only B cell mediated, but is also dependent on follicular T helper cells. To prevent or inhibit this T cell dependent humoral alloresponse, we investigated whether targeting Bcl-6, the transcription factor mediating germinal center formation and the T – B reaction, inhibits this humoral response. For this reason, the effects of the small molecule Bcl-6 inhibitor 79-6 on T and B cell proliferation and differentiation were studied.

Methods: First, the effect on T cell proliferation by 79-6 was tested using a mixed lymphocyte reaction in the presence of different concentrations of 79-6.

Next, we determined whether 79-6 affected the generation of Tfh cells. Magnetic-sorted naïve peripheral CD4 helper T cells were stimulated with anti-CD3/28 along with the polarization cytokines IL-12 and IL-21.

To examine the direct effects of this agent on B cell differentiation, naïve B cells were stimulated with anti-IgM/anti-CD40 and IL-21 in the presence and absence of 79-6.

Results: In the mixed lymphocyte reaction we found a dose dependent effect of 79-6 on T cell proliferation. This includes the proliferation response of the specialized Bcl6+ T helper subset named follicular T cells (Tfh) that are fundamental in the B cell differentiation.

Differentiation of naïve T helper cells under cocktail-stimulated conditions resulted in a large population of “Tfh-like” cells with significantly reduced numbers in the presence of 76-9.

In the presence of the Bcl-6 inhibitor less expression of the B cell memory markers CD27 and CD38 was measured, as well as a decreased formation of plasma cells.

Conclusions: In summary, our studies show promising first results that targeting Bcl-6 transcription affects the functionality of activated T and B cells, thereby preventing the differentiation into B cell plasma blasts, the cell population secreting immunoglobulins.