The thyroid status reprograms T cell lymphoma growth and modulates immune cell frequencies.

UNLABELLED: In spite of considerable evidence on the regulation of immunity by thyroid hormones, the impact of the thyroid status in tumor immunity is poorly understood. Here, we evaluated the antitumor immune responses evoked in mice with different thyroid status (euthyroid, hyperthyroid, and hypothyroid) that developed solid tumors or metastases after inoculation of syngeneic T lymphoma cells. Hyperthyroid mice showed increased tumor growth along with increased expression of cell cycle regulators compared to hypothyroid and control tumor-bearing mice. However, hypothyroid mice showed a higher frequency of metastases than the other groups. Hyperthyroid mice bearing tumors displayed a lower number of tumor-infiltrating T lymphocytes, lower percentage of functional IFN-γ-producing CD8(+) T cells, and higher percentage of CD19(+) B cells than euthyroid tumor-bearing mice. However, no differences were found in the distribution of lymphocyte subpopulations in tumor-draining lymph nodes (TDLNs) or spleens among different experimental groups. Interestingly, hypothyroid TDLN showed an increased percentage of regulatory T (Treg) cells, while hyperthyroid mice displayed increased number and activity of splenic NK cells, which frequency declined in spleens from hypothyroid mice. Moreover, a decreased number of splenic myeloid-derived suppressor cells (MDSCs) were found in tumor-bearing hyperthyroid mice as compared to hypothyroid or euthyroid mice. Additionally, hyperthyroid mice showed increased cytotoxic activity, which declined in hypothyroid mice. Thus, low levels of intratumoral cytotoxic activity would favor tumor local growth in hyperthyroid mice, while regional and systemic antitumor response may contribute to tumor dissemination in hypothyroid animals. Our results highlight the importance of monitoring the thyroid status in patients with T cell lymphomas. KEY MESSAGES: T cell lymphoma phenotype is paradoxically influenced by thyroid status. Hyperthyroidism favors tumor growth and hypothyroidism rises tumor dissemination. Thyroid status affects the distribution of immune cell types in the tumor milieu. Thyroid status also modifies the nature of local and systemic immune responses.

Galectin-3 controls the response of microglial cells to limit cuprizone-induced demyelination.

Galectin-3 (Gal-3) is a ß-galactoside-binding lectin that plays an important role in inflammatory and neurodegenerative diseases. Cuprizone (CPZ)-induced demyelination is characterized by the loss of mature oligodendrocytes (OLG) by apoptosis, myelin sheath degeneration and recruitment of microglia and astrocytes to the lesioned area. We compared CPZ-induced demyelination of 8-week-old Lgals3(-/-) vs WT mice. Lgals3(-/-) mice displayed a similar susceptibility to CPZ-induced demyelination up to the fifth week, as evaluated by MBP immunostaining and electronic microscopy. However, OLG progenitors (OPC) generated in CPZ-treated Lgals3(-/-) mice showed diminished arborization, suggesting decreased ability of these cells to differentiate. Surprisingly, while WT mice experienced spontaneous remyelination in the fifth week of CPZ treatment-even though the CPZ diet was maintained up to sixth week-Lgals3(-/-) mice lacked this capacity and suffered continuous demyelination up to the sixth week, accompanied by pronounced astroglial activation. Moreover, after 2weeks of CPZ treatment, WT and Lgals3(-/-) mice showed lower innate anxiety as compared with respective naive mice, but only CPZ-treated Lgals3(-/-) mice showed decreased locomotor activity and exhibited spatial working memory impairment. Expression of Gal-3 increased during CPZ-induced demyelination in microglia but not in astrocytes. While CPZ-treated WT mice displayed heightened microglial activation associated with ED1 expression and pronounced upregulation of the phagocytic receptor TREM-2b, this effect was not observed in CPZ-treated Lgals3(-/-) mice which, in spite of showing an increased number of microglia, these cells evidenced caspase-3 activation. Our results indicate that Gal-3 is expressed in microglial cells to modulate their phenotype, facilitating the onset of remyelination and OLG differentiation.