mTOR Modulates Lymphocyte Differentiation through T-bet and Eomesodermin in Response to Invasive Pulmonary Aspergillosis in Rats.

BACKGROUND

Aspergillosis infection is common in the patients with insufficient immunity. The role of mammalian target of rapamycin (mTOR), T-box expressed in T-cells (T-bet), and eomesodermin (EOMES) in mediating T lymphocytes differentiation in response to Aspergillus fumigatus infection in immunocompromised rats was investigated in this study.

METHODS

Invasive pulmonary aspergillosis (IPA) of immunosuppressive twenty male rats were established and sacrificed at 24 h (n = 5), 48 h (n = 5), 72 h (n = 5), and 96 h (n = 5) after A. fumigatus infection. In addition, control (n = 5), cyclophosphamide (CTX) (n = 5), and aspergillosis (n = 5) group were also established the tissues and pathology of lung tissue was examined by hematoxylin and eosin staining. CD8+ T-cells was sorted by flow cytometry. Serum mTOR, S6K, T-bet, and EOMES were quantified by enzyme-linked immunosorbent assay.

RESULTS

Histology of lung tissue indicated severe lung tissue injury including infiltration of inflammatory cells, alveolar wall damage or degradation, blood congestion, and hemorrhage in the CTX, IPA, and CTX + IPA rats. Hyphae were seen in the IPA, and CTX + IPA groups. The proportion of CD8+ T-cells was significantly increased in the animals of CTX + IPA. Memory CD8+ T-cells was significantly increased in early stage (24 h and 48 h, P < 0.001), but decreased in the late phase of fungal infection (72 h and 96 h) in the animals of CTX + IPA. In addition, at early stage of fungal infection (24 h and 48 h), serum mTOR (P < 0.001), S6K (P < 0.001), and T-bet (P < 0.05) was significantly higher, while EOMES was significantly lower (P < 0.001), in CTX + IPA group than that in control, CTX alone or IPA alone group. Conversely, serum mTOR, S6K, T-bet, and EOMES showed opposite changed in the late stage (72 h and 96 h). Pearson's correlation analysis indicated that mTOR and S6K were significantly correlated with T-bet (r = 0.901 and 0.91, respectively, P < 0.001), but negatively and significantly correlated with EOMES (r = -0.758 and -0.751, respectively, P < 0.001).

CONCLUSIONS

mTOR may regulate transcription factors of EOMES and T-bet, and by which mechanism, it may modulate lymphocytes differentiation in animals with immune suppression and fungal infection.