Normal tissue homeostasis and impairment of selective inflammatory responses in dendritic cells deficient for ATF6 alpha

The initiation of adaptive immunity relies on the performance of dendritic cells (DCs), which are specialized leukocytes with professional antigen presenting capabilities. As such, the molecular mechanisms safeguarding DC homeostasis are matter of intense research. Sensors of the unfolded protein response (UPR) of the endoplasmic reticulum, a three-pronged signaling pathway that maintains the fidelity of the cellular proteome, have emerged as regulators of DC biology. The archetypical example is the IRE1/XBP1s axis, which supports DC development and survival of the conventional type 1 DC (cDC1) subtype. However, the role of additional UPR sensors in DC biology, such as the ATF6a branch, has not been clearly elucidated. Even though Xbp1 is transcriptionally induced by ATF6a under ER stress, it is unclear if cDCs also co-opt the ATF6a branch in tissues. Here, we examine the role of ATF6a in cDC homeostasis in vivo and upon innate stimulation in vitro. In steady state, animals lacking ATF6a in CD11c(+) cells (Itgax Cre x Atf6 (fl/fl) mice) display normal cDC frequencies in spleen, intestine, liver, and lung. Also, ATF6a deficient cDCs express normal levels of Xbp1 mRNA and additional UPR components. However, a reduction of lung monocytes is observed in Itgax Cre x Atf6 (fl/fl) conditional deficient animals suggesting that ATF6a may play a role in the biology of monocyte subsets. Notably, in settings of DC activation, ATF6a contributes to the production of IL-12 and IL-6 to inflammatory stimuli. Thus, although ATF6a may be dispensable for tissue cDC homeostasis in steady state, the transcription factor plays a role in the acquisition of selective immunogenic features by activated DCs.