Myeloid cell TNFR1 signaling dependent liver injury and inflammation upon BCG infection

Abstract

TNF plays a critical role in mononuclear cell recruitment during acute Bacillus Calmette-Guérin (BCG) infection leading to an effective immune response with granuloma formation, but may also cause tissue injury mediated by TNFR1 or TNFR2. Here we investigated the role of myeloid and T cell specific TNFR1 and R2 expression, and show that absence of TNFR1 in myeloid cells attenuated liver granuloma formation and liver injury in response to acute BCG infection, while TNFR2 expressed in myeloid cells contributed only to liver injury. TNFR1 was the main receptor controlling cytokine production by liver mononuclear cells after antigenic specific response, modified CD4/CD8 ratio and NK, NKT and regulatory T cell recruitment. Further analysis of CD11b + CD3 + phagocytic cells revealed a TCRαβ expressing subpopulation of unknown function, which increased in response to BCG infection dependent of TNFR1 expression on myeloid cells. In conclusion, TNFR1 expressed by myeloid cells plays a critical role in mononuclear cell recruitment and injury of the liver after BCG infection.

CD3+ Macrophages Deliver Proinflammatory Cytokines by a CD3- and Transmembrane TNF-Dependent Pathway and Are Increased at the BCG-Infection Site

“…Here, we demonstrated that a small fraction of circulating monocytes from a healthy donor is typically differentiated into CD3 + MDM, and this cell subpopulation can be divided into TCRαβ + and TCRαβ − phenotypes, both subpopulations has been recently reported in mice and they are negative to CD2 (12). In this regard, we found both proteins and mRNA transcripts for TCR chains in each MDM subpopulation, suggesting that MDM have the ability to express TCR on macrophages under an appropriate stimulus.…”

“…Previously, our group and other have reported that TNF is required to generate TCRαβ + macrophages after in vitro BCG infection, and apparently TNFR1 expression is necessary to maintain the presence of CD3 + myeloid cell (11, 12). Additionally, our data have shown that CD3 + TCRαβ + MDM expressed tmTNF (Figure 3D).…”

“…Moreover, our data show that both CD3 + macrophage subpopulations express HLA class I and II molecules, indicating that they have the ability to present antigens to other cells. Even if we did not evaluate the antigen presentation function, previous reports have shown that CD3 + macrophages are capable of this activity (11, 12). Surprisingly, we find that CD3 + TCRαβ + MDM, but not CD3 + TCRαβ − MDM, expressed CD1a, CD1b, and CD1c, which are non-protein antigen-presenting molecules, suggesting that macrophages are ready to respond using multiple resources against pathogens, which cannot be eliminated by conventional microbicidal mechanisms.…”

“…In this regard, we found both proteins and mRNA transcripts for TCR chains in each MDM subpopulation, suggesting that MDM have the ability to express TCR on macrophages under an appropriate stimulus. In addition, a recent publication has reported that the intensity of expression of CD3 on murine myeloid cells is lower compared to the intensity level on lymphocytes (12). We have to consider that even with an efficient macrophage activation, classic CD3 + T cells will express higher levels of CD3 and TCR than macrophages.…”

“…Using an in vitro model of BCG infection, the authors confirmed that the infection increased the frequency of CD3 + macrophages, and the presence of TNF was essential to maintain this cell subpopulation (11). Recently we demonstrated that BCG infection induces an increase of the recruitment of CD11b + CD3 + phagocytic cells, and it is dependent of TNFR1 expression on myeloid cells, more interesting, we reported there are two CD3 + myeloid subpopulation, one more abundant and phenotypically TCRαβ − and a second TCRαβ + (12).…”