Overall, the expression of these receptors was not only decreased in total thymocytes, but also in CD4/CD8-defined subsets. In contrast, the membrane expression of the chemokine receptors CXCR4 and CCR9 was increased in P. berghei-infected animals, comprising
both immature and mature thymocyte subsets. The chemokine CXCL12 is required by thymocytes to migrate from the cortico–medullary junction to the subcapsular zone, where specific signals from intrathymic microenvironmental niches induce and regulate the earliest stages of thymocyte development.14,23,24 It has also been demonstrated that an enhanced fibronectin expression favours the chemokine sequestration preventing its degradation by matrix metalloproteinases.25 mTOR inhibitor We have found that FK506 datasheet alterations in the ECM pattern were accompanied by increased expression of the chemokine CXCL12 and its respective receptor, the CXCR4 molecule. At the DP stage, thymocytes start to express the CCR9 molecule in response to CCL25 and then migrate towards the medulla. It has been proposed
that the CCL25/CCR9 interaction is necessary to prevent apoptosis during thymocyte development.26 As CCL25 is dramatically decreased in the experimental model presented here, it is reasonable to suppose that DP thymocytes are being missed by apoptosis. This question is under investigation in our laboratory. The mechanisms leading to severe thymic atrophy with changes in the expression of ECM elements and chemokines and their respective
receptors in P. berghei-infected animals are not understood. We believe that the presence of Plasmodium inside the thymus, as reported earlier by our group, is important, and most probably sufficient, to evoke alterations in the thymic microenvironment.5 In fact, we already have strong evidence of the contribution of the leptin hormone and transforming growth factor-β, both thymus-stimulating molecules, for the thymic atrophy during malaria infection. Although it remains to be defined whether there is an intrathymic production of Aurora Kinase leptin, preliminary data indicate a constitutive expression of this molecule by the human thymic epithelium (W. Savino, personal communication). Experiments from our laboratory have shown that the thymi of infected animals present a considerably decreased expression of leptin and transforming growth factor-β and this may be one of the mechanisms leading to severe atrophy observed during this infection (P. R. A. Nagib, J. Gameiro, L. G. Stivanin-Siva, M. S. P. Arruda, D. M. S. Villa-Verde, W. Savino & L. Verinaud, manuscript in preparation). However, the possibility that systemic factors, like cytokines, glucocorticoids and/or other hormones, released during the immune response against the parasite, are also inducing alterations in the thymus cannot be abandoned.