Fig. 1. Roles of T cell subtypes in allograft rejection. Th17 cells promote the infiltration of neutrophils into a graft in an interleukin (IL)-17A-independent pathway [
9]. Neutrophils undergo NETosis to promote allograft rejection [
10,
11]. Th17 cells also activate endothelial cells and fibroblasts. Endothelial cells release chemokines and increase their expression of adhesion molecules. In turn, immune cells are recruited and move from the bloodstream across the endothelial monolayer into the blood vessel wall. This immune cell infiltrate is a hallmark of transplant vasculopathy [
12]. Activated fibroblasts contribute to fibrosis [
13]. Activated endothelial cells and fibroblasts secrete IL-6, promoting the differentiation of Th17 cells [
14]. IL-17 modulates allograft rejection by promoting the maturation of dendritic cells (DCs) [
15]. Compared to immature DCs, which are specialized in endocytosis, mature DCs express higher levels of MHC and costimulatory molecules on their surface for efficient antigen presentation [
16]. Mature DCs present peptides with MHC molecules to activate CD4
+ and CD8
+ T cells. The peptides are produced by the processing of donor MHC molecules. CD8
+ and CD4
+ T cells recognize the peptides via the direct, indirect, and semidirect pathways. In the direct pathway, recipient CD8
+ T cells and CD4
+ T cells engage complexes of MHC molecules and peptides derived from donor MHC molecules on the surface of donor antigen-presenting cells (APCs), and CD8
+ T cells receive assistance from recipient CD4
+ T cells. In the indirect pathway, CD4
+ T cells engage complexes composed of recipient MHC molecules and peptides produced by the processing of donor MHC molecules, thereby forming recipient APC/CD4 T cell couplets. Recipient CD8
+ T cells recognize MHC class Ⅰ: peptide complexes on donor APCs and obtain help from CD4
+ T cells. In the semidirect pathway, CD8
+ T cells recognize intact donor MHC class Ⅰ molecules on recipient APCs presenting donor MHC molecule-derived peptides with recipient MHC Ⅱ molecules to CD4
+ T cells. CD8
+ T cells obtain help from CD4
+ T cells [
17]. Activated CD4
+ T cells differentiate into Th1, Th2, or Th17 cells, depending on the local cytokine environment [
18]. Th1 cells damage allografts via Fas/Fas ligand (FasL)-mediated cytotoxicity and produce interferon (IFN)-γ and the growth factor IL-2, thereby triggering alloreactive CD8
+ cytotoxicity. Th1 cells induce delayed-type hypersensitivity (DTH) by macrophages, which release nitric oxide (NO), tumor necrosis factor (TNF)-α, and oxygen species, leading to allograft damage. Th2 cells secrete IL-4 and IL-5 to activate eosinophils, which release harmful enzymes causing graft destruction. Th2 cells induce the production of alloreactive antibodies by B cells. Th2 cells express IL-4 and IL-10, which inhibit Th1 responses. Activated CD8
+ T cells produce perforin and granzyme. Perforin forms channels in the allogeneic cell membrane, through which granzyme moves into cytoplasm where it induces apoptosis [
19,
20]. In addition to cytotoxicity, CD8
+ T cells regulate effector T cells. CCR7
+CD8
+ T cells reduced the proportion of IFN-γ
+ (Th1) and IL-17
+CD4
+ (Th17) T cells [
21]. An increased Th17-to-regulatory T cell (Treg) ratio contributes to transplant rejection [
22].