Vaccines save millions of lives every year, but not everyone benefits from this protection. For patients suffering from chronic inflammatory diseases, the blockade of TNF is an effective treatment. However, there is evidence that TNF blockers impair vaccine response.
 
Activating antigen-presenting cells (APC) by the vaccine is a prerequisite for  induction of protection. C-type lectin receptors (CLR) are one group of pattern recognition receptors on APC. Clinically used vaccines and adjuvants can contain or lead to the release of ligands recognized by the CLR Mincle. The stimulation of this receptor induces TNF and other pro-inflammatory cytokines. We previously reported that Mincle on macrophages upregulates itself via TNF.
 
Objective:
 
We want to study the importance of TNF signaling in APC for Mincle-dependent Th cell responses. Furthermore, we aimed to test the hypothesis, that the downregulation of Mincle on APC by TNF blocker causally contributes to the reduced immune response.
 
Methods
 
We conditional knocked out the TNFR1 in murine myeloid cells using Lysozyme M-Cre deleter mice. Additionally, we employed a transgenic mouse model with constitutively high Mincle expression to attain a TNF-independent Mincle upregulation. We studied the vaccine responses after immunization with the recombinant Mycobacterium tuberculosis antigen H1 combined with a Mincle-dependent adjuvant CAF01, which is known to induce a robust Th17 response.
 
Results
 
We found that antigen-specific IL-17 production is absent when TNFR1 was knocked out in myeloid cells. The same effect was observed after pharmacological blockade of TNF. In the transgenic mice, which express Mincle independent from its upregulation by TNF, the reduction of the Th17 response by the TNF blocker was partially prevented.
 
 
Conclusion
 
We conclude that regulating CLR expression by TNF defines an underlying mechanism of tuning immune responses to vaccines. This may contribute to impaired immune responses in patients receiving biologicals targeting TNF.