LCMV-immune mice, which had been infected with LCMV-WE 8 wk previ

LCMV-immune mice, which had been infected with LCMV-WE 8 wk previously, Compound Library were able to eradicate the target cells within 24 h, whereas in naïve C57BL/6 mice the target cell population remained stable (Fig. 1E). In H8-CML mice, 29.1±19.5% of the gp33-pulsed target cells were eliminated within 48 h. On the contrary, H8-CML mice depleted of CD8+ T cells were unable to eliminate the target cells. This documented gp33-specific CTL activity in H8-CML mice. Therefore, the majority of

leukemia-specific CTL are exhausted and not detectable in blood by tetramer staining. However, remaining leukemia-specific CTL exist in low frequencies in the spleen and lymph nodes are functionally detectable when analyzed directly in H8-CML mice and they crucially contribute to disease control. To characterize CML-specific CTL in more detail and to overcome the problem of their low frequency, purified p14 TCR transgenic CD8+ T cells (CD45.1+CD8+Vα2+)

specific for LCMV-gp33 were adoptively transferred to H8-CML mice. As shown previously, p14 CD8+ T cells expanded rapidly when transferred learn more to H8-CML mice in blood (Fig. 2A) and spleen (Fig. 2B) 17. As a control, p14 CD8+ T cells were transferred to mice persistently infected with LCMV-Docile. As shown before, the frequency of specific CTL rapidly declined in LCMV-Docile-infected mice due to exhaustion 19. P14 CD8+ T cells transferred to naïve C57BL/6 mice did not proliferate (Fig. 2A and B). Therefore, comparable to a chronic infection with LCMV-Docile, in H8-CML mice with high leukocyte counts only a limited number of specific CTL resisted exhaustion. IL-7 is an important cytokine for T-cell homeostasis. We therefore analyzed the expression of IL-7Rα chain on transferred p14 CD8+ T cells in blood and spleen. In naïve C57BL/6 Cepharanthine mice, p14 CD8+ T cells continued to express high levels of IL-7Rα after transfer in blood and spleen, consistent with their nonactivated phenotype (Fig. 2C and D). On the contrary, p14 CD8+ T cells downregulated IL-7Rα expression after transfer to mice persistently

infected with LCMV-Docile (Fig. 2C and D). Twelve days after transfer, only 5.4±0.6% of p14 CD8+ T cells in the blood of LCMV-Docile-infected mice expressed IL-7Rα. On the contrary, in H8-CML mice, the transferred p14 CD8+ T cells retained IL-7Rα expression on 55.0±11.2% of the transferred p14 CD8+ T cells when analyzed in blood and on 61.1±10.8% of the transferred p14 CD8+ T cells in the spleen (Fig. 2C and D). The level of IL-7Rα expression was independent of the frequency of GFP+ granulocytes (Fig. 2E). However, there was a significant correlation of PD-1 expression and IL-7Rα expression on isolated p14 CTL, indicating that at the same time both, costimulatory and inhibitory signals, determine CTL activation or tolerance (Fig. 2F).

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