T cell exhaustion is associated with antigen abundance and promotes transplant acceptance

Abstract

Exhaustion of T cells limits their ability to clear chronic infections or eradicate tumors. Here, in the context of transplant, we investigated whether T cell exhaustion occurs and has a role in determining transplant outcome. A peptide/MHC tetramer‐based approach was used to track exhausted CD8+ T cells in a male‐to‐female skin transplant model. Transplant of large whole‐tail skins, but not small tail skins (0.8 cm × 0.8 cm), led to exhaustion of anti‐male tetramer+ CD8+ T cells and subsequently the acceptance of skin grafts. To study CD4+ T cell exhaustion, we used the TCR‐transgenic B6 TEa cells that recognize a major transplant antigen I‐Eα from Balb/c mice. TEa cells were adoptively transferred either into B6 recipients that received Balb/c donor skins or into CB6F1 mice that contained an excessive amount of I‐Eα antigen. Adoptively transferred TEa cells in skin‐graft recipients were not exhausted. By contrast, virtually all adoptively transferred TEa cells were exhausted in CB6F1 mice. Those exhausted TEa cells lost ability to reject Balb/c skins upon further transfer into lymphopenic B6.Rag1−/− mice. Hence, T cell exhaustion develops in the presence of abundant antigen and promotes transplant acceptance. These findings are essential for better understanding the nature of transplant tolerance.

Interferon regulatory factor 4 deficiency in CD8+ T cells abrogates terminal effector differentiation and promotes transplant acceptance

“…Full‐thickness tail skins (~1 cm 2 ) from BALB/c mice were transplanted onto B6. Rag1 −/− mice using a previously described method 23 . Skin graft survival was monitored daily up to 100 days.…”

“…Full-thickness tail skins (~1 cm 2 ) from BALB/c mice were transplanted onto B6.Rag1 À/À mice using a previously described method. 23 Skin graft survival was monitored FIGURE 1. IRF4 expression in WT CD8 + T cells is positively correlated with the production of effector molecules.…”

TOXic signaling: How antigen accelerates T cell exhaustion during transplantation

“…In this issue of the American Journal of Transplantation , Zou et al show that the amount of alloantigen present is a key factor in determining the answer to that question 1 . They used the approach of transplanting either large‐size (high antigen load) or small‐size (low antigen load) male skin grafts onto female recipients.…”

“…These conclusions are borne out in the second set of experiments reported in Zou et al 1 To study changes in gene expression following high vs low antigen exposure, they compared RNA‐Seq profile of alloreactive T cell receptor (TCR) transgenic T cells stimulated via either a BALB/c skin graft (low antigen) or following adoptive transfer into a B6 × BALB/c F1 host (high antigen). Although alloreactive T cells isolated from skin graft recipients potently rejected a second skin graft upon adoptive transfer into T and B cell–deficient RAG −/− hosts, alloreactive cells isolated and transferred from B6 × BALB/c hosts failed to do so, and skin graft challenges were tolerated in 100% of recipients.…”

“…Importantly, Tox gene expression is driven by NFAT activation downstream of TCR stimulation, and following nuclear localization Tox binds to the PD‐1 locus via its DNA binding domain to initiate PD‐1 transcription. Thus, the findings of Zou et al suggest a model in which T cell exhaustion following transplantation is programmed by strong TCR stimulation leading to intense NFATc1 expression, which induces Tox upregulation, which in turn initiates PD‐1 transcription 1 …”