Relative Diabetogenic Properties of Islet-Specific Tc1 and Tc2 Cells in Immunocompetent Hosts

Abstract

CD8+ T cells are important effectors, as well as regulators, of organ-specific autoimmunity. Compared with Tc1-type CD8+ cells, Tc2 cells have impaired anti-viral and anti-tumor effector functions, although no data are yet available on their pathogenic role in autoimmunity. Our aim was to explore the role of autoreactive Tc1 and Tc2 cells in autoimmune diabetes. We set up an adoptive transfer model in which the recipients were transgenic mice expressing influenza virus hemagglutinin (HA) specifically in their pancreatic β islet cells (rat insulin promoter-HA mice) and islet-specific Tc1 and Tc2 cells were generated in vitro from HA-specific CD8+ cells of TCR transgenic mice (CL4-TCR mice). One million Tc1 cells, differentiated in vitro in the presence of IL-12, transferred diabetes in 100% of nonirradiated adult rat insulin promoter-HA recipients; the 50% diabetogenic dose was 5 × 105. Highly polarized Tc2 cells generated in the presence of IL-4, IL-10, and anti-IFN-γ mAb had a relatively low, but definite, diabetogenic potential. Thus, 5 × 106 Tc2 cells caused diabetes in 6 of 18 recipients, while the same dose of naive CD8+ cells did not cause diabetes. Looking for the cause of the different diabetogenic potential of Tc1 and Tc2 cells, we found that Tc2 cells are at least as cytotoxic as Tc1 cells but their accumulation in the pancreas is slower, a possible consequence of differential chemokine receptor expression. The diabetogenicity of autoreactive Tc2 cells, most likely caused by their cytotoxic activity, precludes their therapeutic use as regulators of autoimmunity.

IL-23 Drives Pathogenic IL-17-Producing CD8+ T Cells

“…This conclusion is substantiated by the finding that Tc2 cells have much lower diabetogenic potential than do Tc1 cells, despite being as cytolytic as Tc1 cells (44). Direct killing of ␤-cells by Tc1 effectors is regarded as an important, if not crucial, mechanism of T1D induction by CD8 ϩ T cells (45)(46)(47).…”

Heterogeneity in the Differentiation and Function of CD8+ T Cells

“…T cells with low perforin and granzyme B expression in the synovial fluid as compared to peripheral blood of patients (Cho et al ). In contrast, during influenza infection and in autoimmune diabetes, Tc2 cells seem to display high cytotoxic activity (Cerwenka et al 1999;Vizler et al 2000). However, despite cytotoxicity, Tc2 cells were less protective as compared to Tc1 cells during influenza infection, probably because of different homing capacities (Cerwenka et al 1999).…”

“…However, despite cytotoxicity, Tc2 cells were less protective as compared to Tc1 cells during influenza infection, probably because of different homing capacities (Cerwenka et al 1999). Likewise, in an autoimmune diabetes model, pancreas-specific homing, expansion and diabetogenic potential of Tc2 cells were lower as compared to Tc1 cells (Vizler et al 2000). Thus, depending on the type of immune response, Tc2 cells can acquire high or low cytotoxicity and their functional properties strongly differ from those of Tc1.…”

“…Furthermore, Tc2 cells express the lineage-specific transcription factor GATA3 but at lower levels than Th2 cells (Croft et al 1994;Omori et al 2003). Tc2 cells functionally differ from Tc1 cells as shown during influenza infection, in autoimmunity and allergic disorders (Cerwenka et al 1999;Tang et al 2012;Vizler et al 2000). Whereas Tc1 cells are beneficial in allergic airway inflammation, Tc2 cells show only low level of cytotoxicity and aggravate disease.…”

“…Expression of IFN-c is not necessarily connected with the loss of the original cytokines; thus, Tc2 cells producing IFN-c and IL-13 or Tc17 cells positive for IFN-c and IL-17 can be detected. In a diabetes model, Tc2 cells continue to produce IL-4 and IL-10 after transfer but additionally acquire IFN-c production, although at lower level as compared to Tc1 cells (Vizler et al 2000).…”