Immune insufficiency during GVHD is due to defective antigen presentation within dendritic cell subsets

Kate A. Markey, Motoko Koyama, Rachel D. Kuns, Katie E. Lineburg, Yana A. Wilson, Stuart D. Olver, Neil C. Raffelt, Alistair L.J. Don, Antiopi Varelias, Renee J. Robb, Melody Cheong, Christian R. Engwerda, Raymond J. Steptoe, Hayley S. Ramshaw, Angel F. Lopez, Javier Vega-Ramos, Andrew M. Lew, Jose A. Villadangos, Geoffrey R. Hill, Kelli P.A. MacDonald

Alloreactivity after transplantation is associated with profound immune suppression, and consequent opportunistic infection results in high morbidity and mortality. This immune suppression is most profound during GVHD after bone marrow transplantation where an inflammatory cytokine storm dominates. Contrary to current dogma, which avers that this is a T-cell defect, we demonstrate that the impairment lies within conventional dendritic cells (cDCs). Significantly, exogenous antigens can only be presented by the CD8(-) cDC subset after bone marrow transplantation, and inflammation during GVHD specifically renders the MHC class II presentation pathway in this population incompetent. In contrast, both classic and cross-presentation within MHC class I remain largely intact. Importantly, this defect in antigen processing can be partially reversed by TNF inhibition or the adoptive transfer of donor cDCs generated in the absence of inflammation.