Treg activation during allograft tolerance induction requires mitochondrion-induced TGF-β1 in type 1 conventional dendritic cells
Samantha L. Schroth, Lei Zhang, Rebecca T.L. Jones, Kristofor Glinton, Nikita L. Mani, Hiroyasu Inui, Jesse T. Davidson, Samuel E. Weinberg, Navdeep S. Chandel, Maria-Luisa Alegre, Edward B. Thorp
Samantha L. Schroth, Lei Zhang, Rebecca T.L. Jones, Kristofor Glinton, Nikita L. Mani, Hiroyasu Inui, Jesse T. Davidson, Samuel E. Weinberg, Navdeep S. Chandel, Maria-Luisa Alegre, Edward B. Thorp
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Research Article Immunology

Treg activation during allograft tolerance induction requires mitochondrion-induced TGF-β1 in type 1 conventional dendritic cells

Abstract

The role of conventional type 1 DCs (cDC1s) in tolerance induction to solid organ allografts is unknown and important for strategies that seek to prolong allograft viability. Using a murine model deficient in cDC1s, we report cDC1s are required for donor antigen and costimulation blockade (DST + CoB) tolerance induction and survival of cardiac allografts. cDC1 deficiency led to decreases in CD4+CD25+FoxP3+ T cells within allograft and spleen tissue of transplant recipients, and this was found to be antigen specific. Donor antigen stimulation induced TGF-β1 expression in both in vivo cDC1s and in vitro Flt3L-derived cDC1s. Genetic deletion of TGF-β1 in cDC1s prevented induction of antigen-specific CD4+CD25+FoxP3+ T cells and was associated with cardiac allograft rejection. In parallel, single-cell RNA sequencing and metabolic analysis revealed upregulation of cDC1 mitochondrial metabolic signatures after in vivo exposure to DST + CoB. Genetic inactivation of cDC1 mitochondrial metabolism reduced expression of cDC1 TGF-β1, decreased antigen-specific Treg populations, and impaired allograft tolerance. Taken together, our findings implicate cDC1s in strategies to preserve solid organ allografts and also implicate mitochondrial metabolism of cDC1s as a molecular mechanism to enhance the generation of antigen-specific CD4+CD25+FoxP3+ T cells through TGF-β1.

Authors

Samantha L. Schroth, Lei Zhang, Rebecca T.L. Jones, Kristofor Glinton, Nikita L. Mani, Hiroyasu Inui, Jesse T. Davidson, Samuel E. Weinberg, Navdeep S. Chandel, Maria-Luisa Alegre, Edward B. Thorp

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Figure 7

Mitochondrial respiration is increased in cDC1s after exposure to DST + CoB.

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Mitochondrial respiration is increased in cDC1s after exposure to DST + ...
(A) Violin plots of antigen presentation (B2m) and metabolism-related genes (Cox7c, Lars2, Tomm7) in Xcr1hi cDC1s in control and DST + CoB infusion conditions by single-cell sequencing. (B) Gene ontology analysis of differentially expressed genes in Xcr1hi cDC1s after DST + CoB compared with controls by single-cell sequencing. (C) Mitochondrial respiration of sorted splenic cDC1s 48 hours after DST + CoB treatment. n = 4 per group. A/P, antimycin A and piericidin A; 2-DG, 2-deoxy-D-glucose; OCR, oxygen consumption rate. (D) Quantification of basal OCR, max respiration, and respiratory capacity of naive and DST + CoB–treated cDC1s. n = 4 per group. *P < 0.05, **P < 0.01 by 2-tailed unpaired t test.