Abstract
In transplantation, donor dendritic cells (do-DCs) initiate the alloimmune response either by direct interaction with host T cells or by transferring intact donor MHC to host DCs. However, how do-DCs can be targeted for improving allograft survival is still unclear. Here we show CD103+ DCs are the major do-DC subset involved in the acute rejection of murine skin transplants. In the absence of CD103+ do-DCs, less donor MHC-II is carried to host lymph nodes, fewer allogenic T cells are primed and allograft survival is prolonged. Incubation of skin grafts with the anti-inflammatory mycobacterial protein DnaK reduces donor MHC-II on CD103+DCs and prolongs graft survival. This effect is mediated through IL-10-induced March1, which ubiquitinates and decreases MHC-II levels. Importantly, in vitro pre-treatment of human DCs with DnaK reduces their ability to prime alloreactive T cells. Our findings demonstrate a novel therapeutic approach to dampen alloimmunity by targeting donor MHC-II on CD103+DCs.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Animals
-
Antigens, CD / genetics
-
Antigens, CD / metabolism*
-
Basic-Leucine Zipper Transcription Factors / genetics
-
Basic-Leucine Zipper Transcription Factors / metabolism
-
Dendritic Cells / metabolism*
-
Histocompatibility Antigens Class II / genetics
-
Histocompatibility Antigens Class II / metabolism
-
Integrin alpha Chains / genetics
-
Integrin alpha Chains / metabolism*
-
Interleukin-10 / genetics
-
Interleukin-10 / metabolism
-
Mice
-
Mice, Inbred BALB C
-
Mice, Inbred C57BL
-
Repressor Proteins / genetics
-
Repressor Proteins / metabolism
-
STAT3 Transcription Factor / genetics
-
STAT3 Transcription Factor / metabolism
-
Ubiquitin-Protein Ligases / genetics
-
Ubiquitin-Protein Ligases / metabolism*
Substances
-
Antigens, CD
-
Basic-Leucine Zipper Transcription Factors
-
Histocompatibility Antigens Class II
-
Integrin alpha Chains
-
Repressor Proteins
-
SNFT protein, mouse
-
STAT3 Transcription Factor
-
alpha E integrins
-
Interleukin-10
-
MARCH1 protein, mouse
-
Ubiquitin-Protein Ligases