Indirect pathway alloreactive CD4 T cells can provide help to induce cytotoxic CD8 T cells and are known to be the only cells that can provide help to alloreactive B cells (34C36). alloantigens through the direct, indirect or semi-direct pathway (Figure 1). The direct pathway of T cell recognition is unique to allogeneic transplantation, and involves both CD4 and CD8 T cells of the recipient recognizing intact allogeneic major histocompatibility complex (MHC) antigens class II and I, respectively, expressed on the surface of donor cells (Figure 1A). This pathway of allorecognition is considered to be short-lived, especially for HLA class II, due to the limited life-span of donor dendritic cells migrating to lymphoid tissues of the recipient to initiate the immune response. Therefore, the direct pathway T cells are considered to be the predominant mediators of acute cellular rejections in the early post-transplantation period, although MHC expressed on graft parenchyma may as well directly activate T cells at any time after transplantation, contributing to long term injury (20C23). Open in a separate window Figure 1 T cell allorecognition pathways. (A) (Direct pathway) Recipient T cells recognize intact donor alloantigens on Elaidic acid the surface of donor APC. (B) (Indirect pathway) Recipient T cells recognize processed donor allogeneic peptides presented on the context of self MHC antigen by recipient APC. (C) (Semi-direct pathway) Recipient T cells recognize intact donor MHC acquired by recipient APC. MHC, major histocompatibility complex; APC, antigen presenting cell. In comparison to conventional T cell responses to protein antigens, the direct pathway alloimmune response is stronger, likely due to the high frequency of direct pathway alloreactive T cells (24). This allows for measurement of direct pathway alloimmune responses without the need for priming in mixed lymphocyte reactions (MLR). T cell alloimmune responses measured involves CD4 and CD8 T cells with contributions both from na?ve and memory T cell fractions (25, 26). Between 1-10% of circulating T cells in humans are known to be alloreactive as tested by traditional assays (27, 28). Recently, using high Elaidic acid throughput sequencing in combination with MLR IL24 in healthy individuals, Emerson et al. observed an average of 14,000 alloreactive T cell Elaidic acid clones in each experiment they performed. Strikingly, antigen-experienced memory T cell clones made up to 60% of the alloreactive T cell repertoire (29). In addition, the alloreactive memory T cell repertoire could be detected at similar clonal frequencies in a later time point sample when the same allogeneic donor was used for stimulation in MLR, indicating their persistence in circulation. Presence of alloreactive memory T cells in individuals who have never been exposed to alloantigens is supportive for a role of heterologous immunity by which T cells generated in response to infectious or environmental antigens can cross-react with allogeneic MHC antigens (30). Indeed, cross reactivity of virus-induced memory T cells with allogeneic HLA has been shown to be common (7). A classic example of cross reactivity of virus-induced memory T cells with alloantigens is that of HLA-B*08:01 bearing patients who have been exposed to Epstein-Barr virus (EBV) infection showing cross-reactivity to allogeneic HLA-B*44:02 (6, 31). Cross-reactivity of virus-induced T cell receptors (TCR) with alloantigens could be of clinical relevance because they have been shown to directly recognize donor MHC and cause allograft rejection in murine studies. However, a significant impact on transplantation outcome in humans has not been shown so far (32, 33). The indirect pathway is analogous to adaptive T cell responses mounted to common protein antigens, and involves alloreactive T cells of the recipient recognizing allogeneic MHC class I or class II as processed peptides presented in the context of self MHC class II (Figure 1B). Indirect pathway alloreactive CD4 T cells can provide help to induce cytotoxic CD8 T cells and are known to be Elaidic acid the only cells that can provide help to alloreactive B cells (34C36). The indirect pathway of T cell allorecognition is considered to.