Diversity of the CD4 T Cell Alloresponse: The Short and the Long of It

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.

Prolongation of allograft survival by passenger donor regulatory T cells

“…6,28 Such a use of third-party T-regs to block host humoral alloimmunity would be distinctly different from proposed strategies that differentiate/expand T-regs with self-restricted specificity for alloantigen from the individual's endogenous T cell population, 25,33 and may offer a particular advantage. 37 This approach may have wider uses beyond transplantation. [34][35][36] Thus, for maximum effectiveness, recipient-derived T-regs would need to recognize the relevant allopeptide epitope presented by host MHC class II.…”

Evolving Approaches in the Identification of Allograft-Reactive T and B Cells in Mice and Humans

“…Of these, CD25 16,17 , CD69 17,18 , CD71 16,17 , CD134 19 , CD137 19,20 , CD154 19 and LFA1α 21 have been used in transplantation to identify alloreactive T cells. The glycoproteins CD44 21–23 or CD45 isoforms 24 , markers of antigen experience, are also used to distinguish naive from effector and memory cells. Markers of cell-cycle entry such as Ki67 can also identify recently activated T cells 23 .…”

“…The glycoproteins CD44 21–23 or CD45 isoforms 24 , markers of antigen experience, are also used to distinguish naive from effector and memory cells. Markers of cell-cycle entry such as Ki67 can also identify recently activated T cells 23 . Additionally, labeling responder PBMCs with intracellular dyes such as carboxyfluorescein succinimidyl ester (CFSE), whose fluorescence intensity is halved with each cell division, has been used to identify proliferating donor-reactive T cells following culture in an MLR 25 .…”

“…Mice bearing Tg TCRs specific to antigens restricted to presentation on either donor or host MHC have been used to study direct or indirect allorecognition, respectively. Comparison of direct and indirect T cells in a mouse model of chronic heart allograft rejection has shown that direct recognition of alloantigen occurs for a brief time following transplantation, whereas indirect allorecognition can be more long-lived provided that donor antigen remains available for processing and presentation 23 .…”

Current status of alloimmunity

“…While donor MHC-peptide complexes is directly recognized by recipients' T cell in the former, allo-MHC is processed and re-presented by recipient antigen-presenting cells (APCs) in the indirect pathway, which plays a dominant role in the long term based on the continuous shedding of alloantigen from the graft. By using an adoptive transfer model of transgenic T cells in a murine chronic cardiac transplant model, Ali et al elegantly showed that the direct-pathway CD4 T cells are short lived, mostly due to the quick elimination of donor-derived APCs, while the indirect-pathway CD4 T cell responses are persistent and heterogeneous in terms of duration and sites, depending on the targeted alloantigen (1): donor-MHC I-specific responses taking place in allograft parenchyma last long, whereas anti-MHC II responses decay earlier due to donor APCs eradication. These findings highlight the importance of restraining the indirect allorecognition, in particular against donor MHC class I molecules, to prevent chronic cellular-mediated rejection.…”