IL-21 is essential for the optimal control of Mycobacterium tuberculosis infection (INC2P.416)

Abstract

Abstract IL-21 is a Th17 cytokine and is known for its anti-tumor and anti-viral effects. In the current study using IL-21receptor (IL-21r-/-) and IL-21 knockout (IL-21-/-) mice, we determined the role of IL-21 and IL-21r in Mycobacterium tuberculosis (M. tb) infection. Around 50% of M. tb H37Rv infected IL-21r-/- mice died in six months compared to no deaths in infected control mice. M. tb infected IL-21r-/- mice have enhanced bacterial burden (7.3 ± 1.0 x 106 vs. 0.7 ± 0.08 x 106,p<0.001), reduced infiltration of CD4+ T-cells (0.9 ± 0.01 x 105 vs. 1.4 ± 0.03 x 105, p<0.001), increased frequency of PD-1,2B4,CD160 & EOMES (transcription factor) and reduced frequency of IL-12Rβ positive T-cells in lungs compared to wild type M. tb infected mice. T-cells from M. tb infected IL-21-/- mice proliferated less, produced less IFN- γ in response γ-irradiated M. tb and expressed more EOMES compared to wild type M. tb infected mice, and this was reversed by recombinant IL-21. EOMES siRNA increased IFN- γ production (p=0.007) and IL-12Rβ expression by T-cells of M. tb infected wild type mice. We also found T-cells from M. tb infected IL-21-/- mice enhance production of IFN-α (p=0.01), IL-10 (p=0.01), reduce IL-12 (p=0.02) and IL-1β (p=0.04) expression by M. tb infected macrophages and were unable control bacterial growth in macrophages compared to T-cells from M. tb infected wild type mice. The sums of our findings suggest that IL-21 and IL-21r are essential for optimal control of M. tb in mice