ATF3 distinguishes between innate and adaptive immunity
JOURNAL OF INVESTIGATIVE DERMATOLOGY(2023)
摘要
To answer whether innate immunity causes autoinflammation or initiate adaptive response, we focused on ATF3, which functions as a regulator in early innate signaling. Therefore, we studied the impact of ATF3 on innate and adaptive response in vivo. In previous works we observed opposing effects of ATF3 on either innate or adaptive immune responses. We further evaluated a relevance for T cell-mediated immunity in a context of contact hypersensitivity. Atf3ko or wt mice were sensitized with TNCB and challenged. After the challenge, T cell-associated cytokines Il2 and Il4 were induced in the wt mice and almost at background in Atf3ko mice. Tissue from Atf3ko mice showed reduced levels of Ifn and Cxcl10. Il6 was increased in Atf3ko, while the mRNA levels of the IL-1 cytokine family members were similar in Atf3ko and wt mice. Coinciding, Atf3ko mice showed a stronger infiltrate of neutrophils. We further analyzed draining lymph nodes via FACS and revealed delayed migration of DCs in ATF3ko mice. Further, Atf3-deficient DCs showed an irregular shape with dysregulated actin formation in contrast to wt DCs. To determine the effect of ATF3 on adaptive immune responses, we analyzed CD4+ cells isolated from draining lymph nodes. Indeed, Il2 and Il4 mRNA was induced in CD4+ T cells from wt mice but not from Atf3-/- mice, and CD4+ T cells from Atf3-/- mice also showed significantly reduced levels of Ifng mRNA as compared to controls. Investigating the role of ATF3 in antigen presentation, we analyzed co-cultures of DCs from Atf3ko and wt mice with OTII-CD4+ T-helper cells. As a constant, we observed lower levels of Ifn, Il2 and Il4 in the co-culture with Atf3ko DCs compared to the controls. In summary, our data suggest that the suppression of ATF3 does not stimulate both innate and adaptive immunity, but promotes a state of autoinflammation with enhanced neutrophil recruitment DC dysfunction and suppressed T cell activation.
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关键词
atf3 distinguishes,immunity
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