The inhibitory effect of tacrolimus and sirolimus on the differentiation of T cells into follicular helper-like T cells

R. Kraaijeveld, Y. Li, L. Yan, K. de Leur, M. Dieterich, A.M.A. Peeters, L. Wang, Y. Shi, C.C. Baan

Thursday 14 march 2019

13:35 - 13:37h at Tropentheater

Categories: Klinisch/Basaal, Parallelsessie

Parallel session: Parallelsessie XV – Basaal / Klinisch 2

Background: The effect of immunosuppressive drugs on the generation of T follicular helper (Tfh) cells, specialized in supporting B cell differentiation, is largely unknown. We examined whether the calcineurin inhibitor tacrolimus (TAC) and the mTOR inhibitor sirolimus (SRL) inhibit differentiation of Tfh cells and impact subsequent B cell functions.

Methods: Isolated naïve T cells were polarized to Tfh-like cells in the presence of TAC or SRL. To demonstrate the functionality of the generated Tfh cells we co-cultured these cells with isolated B cells in the presence of alloantigen, and analyzed the Tfh-like cells for B cell help function. Tfh-like cells were defined as CD4+CXCR5+T cells, which also express PD-1 and ICOS.

Results: Both TAC and SRL significantly inhibited the differentiation into Tfh-like cells. Therapeutic concentrations of TAC and SRL markedly reduced the percentage of CD4+CXCR5+PD-1+and CD4+CXCR5+ICOS+Tfh cells compared to controls. In addition, the T cells grown in the presence of TAC and SRL expressed less IL-21 and were less potent in providing B cell help. Tfh dependent alloantigen activated B cell proliferation and differentiation into plasma cells and transitional B cells was inhibited by both TAC and SRL.

Conclusions: TAC and SRL inhibited the differentiation of naïve T cells into functional Tfh-like cells, a finding that can be extrapolated to immunosuppressive regimens in transplant patients.