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. 2020 Sep 2;11:1838. doi: 10.3389/fimmu.2020.01838

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Copyright © 2020 Pérez, de Meis, Rodriguez-Galan and Savino.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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(A) Simplified schematic model of thymocyte migration across the thymic lobule. (B) Conveyor belt representation of thymocyte maturation and the processes of positive and negative selection. BM-derived precursors enter through blood vessels located in the cortico-medullary junction (CMJ). The most immature thymocytes originated from these pluripotent precursors are called DN cells, since lack CD4 and CD8. DN cells go through four stages (DN1-DN4) defined by the expression of CD44 and CD25. During differentiation, DN cells migrate from the CMJ to the subcapsular zone of the thymus. Cell precursors are irreversibly committed to the T-cell lineage during the passage from DN1 to DN2 state. In this stage, cells that are successful in the rearrangement of the β-chain of the T-cell receptor (TCR) are selected for further maturation steps. After passing by the DN4 stage, survived thymocytes are converted into double-positive (DP) thymocytes by acquisition of CD4 and CD8. In this step occurs the rearrangement of the genes encoding the α-chain of the TCR. Double-positive thymocytes undergo are positive and negative selection, and their destinies are determinated by the interaction with the thymic epithelial cells (TECs). Once positively selected, tjey are able to generate single-positive (SP) cells. In this step, thymocytes move away from de cortex and enter the medulla. A large percentage of thymocytes die by neglect, due to the non-functionality of their TCRs. The remaining cells interact with different degrees of affinity with their specific antigens. A strong affinity prompts apoptosis and subsequent clonal deletion. An intermediate affinity may induce regulatory T cells. Also, T_IM-CD8: Innate memory CD8 cells appear. Low affinities allow their differentiation to SP cells. Finally, mature thymocytes reach the CMJ and exit to the periphery as RTEs. In most of these stages, diverse alterations are observed after T. cruzi infection, which are indicated in the figure by red teardrop pointers: (1) Decreased entrance of BM-dP; (2) Retention of thymocytes in the DN1 state; (3) DN abnormal escape; (4) Enhanced DP thymocyte apoptosis, mainly driven by enhanced levels of glucocorticoids. (5) DP abnormal escape, with many of them carrying prohibited TCR-Vβ, also exhibiting an activated phenotype; (6) tTreg accumulation among SP thymocytes; (7) Increase in T_IM-CD8 cells; (8) Increase in RTE proportions, with many of them carrying prohibited TCR-Vβ; (9) Increased deposition of ECM molecules in both cortex and medulla, (10) Abnormal presence of FoxP3⁺ cells in the cortical area. cTEC, cortical thymic epithelial cells; mTEC, medullary thymic epithelial cells; DC, dendritic cell; Mf, macrophages; DN, double negative; DP, Double positive; SP, single positive; BM-dP, Bone marrow-derived precursors; CMJ, Corticomedullary junction; RTEs, Recent thymic emigrants; T_IM-CD8, Innate memory CD8⁺ cells; SCZ, Subcapsular Zone (SCZ); ECM, extracellular matrix.