Characteristics of direct and indirect activation of human T cells against allogeneic and porcine xenogeneic cells/peptides

Abstract

Abstract: The immunological consequences of direct versus indirect activation of T lymphocytes is of considerable interest both in allogeneic and in xenogeneic transplantation. In this paper, the activation of human T cells by allogeneic and xenogeneic porcine antigen‐presenting cells (APC) (direct activation), or by donor‐derived peptides presented on autologous APC (indirect activation) was studied in vitro. The direct activation of purified human T lymphocytes by allogeneic and xenogeneic porcine stimulator cells led to marked proliferative responses, IL‐2 and IFN‐γ production. The ratio of CD4/CD8 of responsive cells upon direct activation was the same for allogeneic and xenogeneic stimulation. Also, the CD25 expression on total and on CD8+ lymphoblasts was similar in allogeneic and xenogeneic responses. The frequency of alloreactive and xenoreactive CTLp following direct activation was 7.7 ± 1.4 / 104 and 3.7 ± 1.3 / 104, respectively. Direct activation of proliferation and IL‐2 and IFN‐γ production in both experimental situations was completely blocked by Cyclosporin A (CsA). 15‐deoxyspergualin (DSG), which is thought to prevent antigen processing, had little effect. Thus, when it comes to direct activation of T lymphocytes xeno‐ and allospecific responses were qualitatively and quantitatively comparable.However, some differences between allogeneic and xenogeneic responses were observed when indirect activation was studied using stimulator cells from peripheral blood depleted of both adherent cells and of SLA class II positive cells or when human allogeneic or xenogeneic fibroblasts were used as stimulators. Indirect activation following recognition of alio‐ or xenogeneic peptides in a responder HLA‐restricted fashion resulted in proliferation, IL‐2 and IFN‐y production, albeit lower than in direct combinations. Indirect activation also induced a lower proportion of CD25+ lymphoblasts than direct activation. Furthermore, indirect xenoactivation resulted preferentially in proliferation and CD25 expression in the CD4+ cell population, and in contrast to direct activation, not only CsA but also DSG inhibited activation. Thus, our findings indicate that direct and indirect activation of human responder T cells stimulated by allogeneic and/or xenogeneic porcine cells/peptides results in immune responses with similar characteristics. Only the proliferation of CD8+ cells and their expression of CD25 and of functional IL‐2 receptors was weaker following xeno‐ than alloactivation, reasons for which are discussed. We conclude that indirect activation of T cell reactivity against xenogeneic peptides leads to an efficient immune response, likely to be of clinical importance for rejection of xenogeneic transplants devoid of professional antigen‐presenting cells.