Work

Immune Insufficiency After Experimental Transplantation Is Due to Defective Antigen Presentation Within Dendritic Cell Subsets

Year: 2012

Type: article

Abstract: Alloreactivity after transplantation is associated with profound immune suppression and consequent opportunistic infection results in high morbidity and mortality. This immune suppression is most dramatic during graft–versus–host disease (GVHD) after bone marrow transplantation (BMT) where an inflammatory cytokine storm dominates. We used the B6 (I-Ab/I-E-/-) → BALB/c (I-Ad/I-Ed) BMT model to track antigen specific responses induced by donor APC. Bone marrow grafts were either T cell depleted (non-GVHD) or replete (GVHD) and derived from wild-type or CD11c.OVA transgenic (Tg) donors. We determined the extent of antigen presentation by quantifying CFSE dilution of adoptively transferred TEa Tg T cells (which respond to host I-Ed presented in donor I-Ab) and OT-II Tg T cells (which respond to OVA-derived peptide). GVHD induced a marked defect in antigen presentation of both alloantigen and nominal antigens. By utilizing CD11c.DTR Tg grafts and DC-depletion with diphtheria toxin we demonstrated that conventional DC (cDC) were the critical donor cell presenting alloantigen during GVHD. Surprisingly, number, phenotype and phagocytic/proteolytic function of these cells were all equivalent in the GVHD and non-GVHD settings. However, cDC from mice with GVHD failed to present OVA Ag within MHC II to OT-II T cells, confirming a DC specific defect during GVHD. In contrast, both classical and cross presentation within MHC class I remained intact. Analysis of cDC subsets revealed that the CD8neg donor cDC were the critical cell population for class-II mediated Ag presentation and that this specific sub-population was defective during GVHD. This defect is two-fold, and is caused by both a functional impairment in class II presentation in the CD4negCD8neg cDC population, and a concurrent failure of development in the CD4+CD8neg population. Importantly, the functional defect in antigen processing within MHC class II can be reversed by TNF inhibition or the adoptive transfer of donor cDC generated in the absence of inflammation.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2011.12.066