Objectives: Thyroid hormones exert immunomodulatory activities and the thymus is one of their target organs. We previously showed that triiodothyronine (T3) modulates thymic hormone production and extracellular matrix (ECM) expression by mouse thymic epithelial cells (TEC). This concept is enlarged herein by studying the effects of T3 in human TEC preparations including primary cultures derived from thymic nurse cell complexes, as well as human and murine TEC lines. Methods and Results: We observed that in all cases, ECM ligands and receptors (such as fibronectin, laminin, VLA-5 and VLA-6) are enhanced in vitro, as ascertained by immunocytochemistry, ELISA and cytofluorometry. Moreover, thymocyte adhesion to these TEC preparations is augmented by T3. Interestingly, TEC-thymocyte adhesion is also upregulated when thymocytes from T3-treated mice adhere to untreated TEC cultures. Such an enhancing effect of T3 upon TEC-thymocyte interactions is likely due to the increase in the expression of ECM ligands and receptors, since it is prevented when T3-treated TEC cultures are incubated with anti-ECM antibodies prior to the adhesion assay. We then tested whether T3 could modulate interactions between thymocytes and nonepithelial microenvironmental cells, exemplified herein by the phagocytic cells of the mouse thymic reticulum. In fact, in vitro treatment of these cells with T3 increases ECM ligands and receptors and augments their ability to adhere to thymocytes. Lastly, using immunochemistry-based assays, we showed the presence of the nuclear T3 receptor in all thymic microenvironmental cell preparations. Conclusion: Our data show that T3 upregulates ECM-mediated heterocellular interactions of thymocytes with distinct thymic microenvironmental cells, in both humans and mice.
Growth hormone (GH) has been shown to stimulate T cell development. However, its mechanisms of action on the peripheral T cell pool remain unknown. To address this question, intrathymic injection of GH in combination with fluorescein isothiocyanate (FITC) was used to assess the effects of GH on T cell trafficking from the thymus to the periphery. GH promoted a significant increase in the percentage and differential distribution of thymic CD4+CD8–FITC+ cells in secondary lymphoid organs. A significantly higher percentage of CD4+CD8–FITC+ cells was observed in the lymph nodes, while a relative decrease of these cells was found in the spleen. Moreover, we verified that GH treatment resulted in increased numbers of CD62L+CD4+CD8–FITC+ T cells in the lymph nodes, while the same treatment resulted in a decline in the percentage of VLA-6+CD4+CD8–FITC+ T cells in the spleen. Together, these findings suggest that GH is a potent immunoregulatory molecule which selectively stimulates the preferential homing of CD4+CD8– thymic emigrants to the subcutaneous lymph nodes possibly via the differential expression of CD62L and VLA-6.
SummaryMultidrug-resistant tuberculosis (MDR-TB) is known as having a poor prognosis with a weak response to therapy and very high death rates. The aim of this work was to assess the immune response to the RD1-encoded antigen ESAT-6 of Mycobacterium tuberculosis in MDR-TB patients and compare to non-resistant (NR) TB patients and healthy controls (HC). Evaluation of interferon (IFN)-g g g g production showed that, although 55% of the MDR patients were responsive to ESAT-6, they produced lower IFN-g g g g levels (553 ± ± ± ± 11 pg/ml) when compared to NR-TB (1179 ± ± ± ± 163 pg/ml; P < < < < 0·05) but not to controls (412 ± ± ± ± 65·7 pg/ml). Differences in the response to ESAT-6 and to its overlapping peptides mixture were also significant between MDR versus treated pulmonary NR-TB. Furthermore, a very low rate of response to PPD (23·5%) and to Ag85B (33·3%) was noted in MDR-TB patients as compared to the other groups. To determine the inflammatory response in patients' groups, detection of tumour necrosis factor (TNF)-a a a a was assessed in their sera before and during chemotherapy. Mean TNF-a a a a levels in MDR-TB (43·8 ± ± ± ± 9 pg/ml) paralleled those found in treated pulmonary, and it was significantly different ( P < < < < 0·05) from the values found in untreated NR and HC. Interestingly, secretion of IFN-g g g g and TNF-a a a a were predominant in MDR patients who presented with bilateral pulmonary lesions and lung cavitation. The present data indicate that the overall immune response to mycobacterial antigens is decreased in resistant TB and the major role inflammatory cytokines may play in perpetuating pulmonary tissue damage.
This study confirmed the feasibility of obtaining ex vivo macrophages from leprosy lesions and keeping them in long-term culture. This procedure may open new pathways to studying the interaction between M. leprae and human macrophages, which might, in turn, lead to the development of therapeutic tools capable of overcoming the specific anergy found in patients with MB leprosy.
The functioning of the immune system partially relies on T‐cell exportation from the thymus, the major site of T‐cell differentiation. Although the molecular mechanisms governing this process begin to be elucidated, it is not clear if thyroid hormones can alter the homing of recent thymic emigrants (RTE) to peripheral lymphoid organs. Herein, we investigated whether triiodothyronine (T3) could influence the homing of thymus‐derived T cells. For that we used intrathymic injection of T3 in combination with fluorescein isothiocyanate (FITC) to trace, 16 h later, FITC+ cells, termed RTE, in peripheral lymphoid organs. We observed that T3 stimulated thymocyte export, increasing the frequency of CD4+ RTE and CD8+ RTE in the subcutaneous and mesenteric lymph nodes. By contrast, the relative numbers of CD4+ RTE in the spleen were decreased. T3 also changed the differential distribution pattern of CD4+ RTE, and to a lesser extent CD8+ RTE in the peripheral lymphoid organs. Moreover, the expression of extracellular matrix (ECM) components, such as laminin and fibronectin, which are known to be involved in T‐cell migration, increased in the lymph nodes but not in the spleen following intrathymic T3 treatment. In conclusion, our data correspond to the first demonstration that in vivo treatment with thyroid hormone stimulates thymic T‐cell homing and T‐cell distribution in peripheral lymphoid organs.
Triiodothyronine (T3) exerts several effects on thymus physiology. In this sense, T3 is known to stimulate thymic microenvironmental cells to enhance the production of extracellular matrix (ECM) moieties, which are relevant in thymocyte migration. Here, we further investigated the in vivo influence of T3 on ECM production, as well as on ECM‐related T‐cell migration events. For this, BALB/c mice were subjected to two protocols of T3 treatment: long‐term (30 days) i.p. daily T3 injections or short‐term (16 h) after a single T3 intrathymic injection. These two treatments did promote an enhancement in the expression of fibronectin and laminin, in both cortex and medullary regions of the thymic lobules. As revealed by the long‐term treatment, the expression of ECM protein receptors, including VLA‐4, VLA‐5 and VLA‐6, was also increased in thymocyte subsets issued from T3‐treated mice. We further used thymic nurse cells (TNC) as an in vitro system to study the ECM‐related migration of immature thymocytes in the context of thymic epithelial cells. Even a single intrathymic injection of T3 resulted in an increase in the ex vivo exit of thymocytes from TNC lymphoepithelial complexes. Accordingly, when we evaluated thymocyte migration in transwell chambers pre‐coated with ECM proteins, we found an increase in the numbers of migrating cells, when thymocytes were derived from T3‐treated mice. Overall, our data show that in vivo intrathymic short‐term i.p. long‐term T3 treatments are able to modulate thymocyte migration, probably via ECM‐mediated interactions.
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