Abstract
SummaryMHC alloantigen is recognized by two pathways: “directly,” intact on donor cells, or “indirectly,” as self-restricted allopeptide. The duration of each pathway, and its relative contribution to allograft vasculopathy, remain unclear. Using a murine model of chronic allograft rejection, we report that direct-pathway CD4 T cell alloresponses, as well as indirect-pathway responses against MHC class II alloantigen, are curtailed by rapid elimination of donor hematopoietic antigen-presenting cells. In contrast, persistent presentation of epitope resulted in continual division and less-profound contraction of the class I allopeptide-specific CD4 T cell population, with approximately 10,000-fold more cells persisting than following acute allograft rejection. This expanded population nevertheless displayed sub-optimal anamnestic responses and was unable to provide co-stimulation-independent help for generating alloantibody. Indirect-pathway CD4 T cell responses are heterogeneous. Appreciation that responses against particular alloantigens dominate at late time points will likely inform development of strategies aimed at improving transplant outcomes.
Highlights
Chronic rejection, leading to late graft loss, remains the major challenge for solid organ transplantation
In the ‘‘direct pathway,’’ alloreactive T cells recognize intact donor MHC molecules presented on the surface of donor antigen-presenting cells (APCs), whereas in the ‘‘indirect pathway,’’ T cells recognize major, and minor, histocompatibility antigens that have been acquired by recipient APCs, processed and presented as self-MHC-restricted peptides (Ali et al, 2013; Jiang et al, 2004)
Allograft Vasculopathy (A) B6.Kd, bm12, and ABOIE mice were intercrossed to create a ‘‘bm12.kd.IE’’ donor strain that differed from the C57BL/6 recipient strain at the classical MHC class I H-2K and MHC class II
Summary
Chronic rejection, leading to late graft loss, remains the major challenge for solid organ transplantation. The indirect CD4 T cell allorecognition pathway is generally regarded as a single entity but is instead presumably a culmination of multiple responses against potentially every disparate alloantigen expressed by the graft. Given that these antigens are likely to be expressed at different concentrations in the graft and, in the case of MHC class II, predominantly expressed on the hematopoietic components of the graft, it is plausible that the duration and strength of indirect-pathway responses differ depending on the target alloantigen.
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