CD4^hiCD8^lowDouble-Positive T Cells Are Associated with Graft Rejection in a Nonhuman Primate Model of Islet Transplantation

Abstract

Peripheral CD4/CD8 double-positive (DP) T cells are associated with autoimmune disorders, cancer, and viral infection. However, the relationship between organ transplantation and DP T cells is unclear. Here, we examined the functional characteristics of peripheral DP T cells and analyzed their significance with respect to islet graft rejection in a nonhuman primate model of islet transplantation. DP T cells were functionally equivalent to conventional CD4 and CD8 T cells in terms of helper and cytotoxic activity, respectively. DP T cells expressed high levels of CXCR5 and PD-1 and secreted IFN-γ, IL-4, and IL-21 in amounts equivalent to those secreted by CD4 or CD8 T cells; also, they produced large amounts of granzyme B and perforin. In addition, under steady-state conditions, DP T cells expressed eomesodermin (Eomes) and promyelocytic leukemia zinc finger (PLZF) proteins, both of which act as transcription factors in innate/memory-like T cells. The number of peripheral DP T cells in the islet transplantation model was high in the group that experienced graft rejection; this was not the case in the long-term survival group. Interestingly, numbers of effector memory T cells (TEM) within the DP T cell population increased significantly during islet graft rejection, as did those of TEM within the cytotoxic CD8 T cells. Furthermore, the most conspicuous of which was the increase of CD4hiCD8low T cell subpopulation at that point. Taken together, the data suggest that peripheral DP T cells showing an innate/memory-like phenotype have both helper and cytotoxic activity in vitro and that they may act as a novel biomarker for graft rejection after islet transplantation.

Cellular heterogeneity of circulating CD4+CD8+ double-positive T cells characterized by single-cell RNA sequencing

“…Additionally, CD4 CTL-like cells, which exhibit cytotoxic properties, were also identi ed in the NKG2D + cells of the CD4 hi CD8 lo fraction. Given these cytotoxic characteristics, these data support previous ndings that peripheral DP cell populations are increased under chronic in ammatory conditions, such as transplantation 4 and viral infection 9 , as well as in cancer patients 40 .…”

“…Nevertheless, the phenotypic properties and functional roles of circulating DP T lymphocytes have not been characterized completely. For instance, in a previous study 4 , we found that some DP T cells express signi cant levels of promyelocytic leukemia zinc nger (PLZF) 15 and eomesodermin (Eomes) 16 , both markers of innate lymphocytes, when compared with CD4 SP and CD8 SP T cells. In this respect, DP T cells may be another type of innate-like T cell and so may be considered to be cells with similar characteristics.…”

“…In addition to CD4 or CD8 single-positive (SP) T cells, which originate in the thymus, where they also commit to a certain lineage and undergo positive or negative selection, CD4 + CD8 + double-positive (DP) T cells that express both CD4 and CD8 co-receptors simultaneously are present in peripheral blood and tissues (e.g., lymph nodes, liver, and spleen) 4,5 . Many reports reveal that this population is associated with several pathological conditions, including cancer 6,7 , autoimmune disorders 8 , graft rejection 4 , and viral infections 9,10 . In most cases, these DP T cells are found in abundance in the blood and/or target organs, suggesting that they are involved in the pathological process.…”

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“…Данное наблюдение подтверждает недавние результаты исследования (Y.J. Choi et al, 2018), указывающие на роль периферических ДП Т-клеток в модели трансплантации островков поджелудочной железы. Было обнаружено увеличение уровня CD3 + CD4 + CD8 + Т-лимфоцитов в экспериментальной группе животных, в которой наблюдалось отторжение трансплантата.…”

Cd3+cd4+cd8+ T-Lymphocytes Count in Prognosis of Early Kidney Allograft Dysfunction

“…Что касается роли данной субпопуляции в трансплантологии, некоторыми авторами показано, что увеличение количества ДП Т-клеток в модели трансплантации островков поджелудочной железы было ассоциировано с отторжением трансплантата. Учитывая полученные данные, авторы предположили, что периферические ДП Т-клетки, обладающие как хелперной, так и цитотоксической активностью in vitro, могут выступать в качестве нового биомаркера для диагностики отторжения [7].…”