The deletion of Interleukin-4 receptor alpha (IL-4Rα) signalling on T cells increased host susceptibility to TB.

Dr Suraj Parihar, University of Cape Town (UCT), South Africa

Protective immunity to TB is dependent on the ability of the host to mount a robust T cell response. The Th2 response, associated with IL-4Rα mediated signalling, remains largely overlooked in TB. Here, we investigated the T cell-specific role of IL-4Rα in TB disease by making use of the T cell-specific knockout model, iLCKCreIL-4Rα-/lox. We found that the absence of IL-4Rα on T cells results in a delay in the recruitment of T cells to the lung in the acute phase of infection. Consequently, the bacilli establish and proliferate in the lung, as shown by increases in lung mycobacterial burden at both acute and chronic stages of infection. This was accompanied by reduced alveolar space in the lungs of iLCKCreIL-4Rα-/lox mice. We found that deletion of IL-4Rα on T cells had no role in the dissemination of TB in the spleen. Importantly, increased lung burdens resulted in decreased survival of T cell-specific IL-4Rα mice. Despite enhanced susceptibility, the absence of IL-4Rα on T cells showed increased T-bet and RORγt transcription factors, indicating stronger host-protective Th1 and Th17 responses, respectively. In humans, stimulation of PBMC with Mtb antigens ex vivo revealed that the mRNA transcripts IL-4Rα were significantly upregulated in active TB patients. Altogether, we showed that intact IL-4Rα on T cells is required for host protection during TB.