Schema of T cell development in the thymus and of the proposed role of extrathymic DP T cells. Left figure: progenitors of CD4⁻CD8⁻ (DN) T cells enter the thymus from bone marrow via the large blood vessels at the border between cortex and medulla and move towards the capsule of the organ. Rearrangement at the T cell receptor (TCRβ): γ and δ gene loci commence, and strong TCR signaling favors development of the γ δ T cell lineage, while weak TCR signals lead to α β commitment [20]. Only cells that rearrange their T cell receptor β (TCRβ) chain proliferate extensively and give rise to CD4⁺CD8⁺ double-positive (DP) thymocytes. These cells occupy much of the cortex and move around slowly while their TCRα chains are rearranged. During this phase, weak interaction in the cortex between the newly formed T cell receptors (TCRs) on cortical thymocytes and self-peptides bound to major histocompatibility complex (MHC) proteins on cortical thymic epithelial cells (TECs) leads to survival and maturation of the thymocytes. Thereafter only T cells bearing TCR with a low avidity for any of the self-peptide-MHC class I or II molecules presented on thymic epithelial cells (TECs) are subjected to selection, becoming CD8⁺ or CD4⁺ single-positive (SP) T cells [18]. Other cells with high avidity for any of the self-peptide-MHC class I or II molecules die by apoptosis via negative selection in the central medullary region of the thymus or are alternatively differentiated into regulatory T cells [21, 22]. Some DP thymocytes express CD1a, which binds self-glycolipids, and other DP thymocytes that are able to interact with these cells enter the NKT lineage. Most NKT cells that exit the thymus become mature in the periphery. Mature cells within the thymus can either emigrate from the thymus or remain for a period in that organ [23]. Right figure: in a pathological setting, the severe thymic atrophy leads to release of activated DP T cells to the periphery. In Chagas disease, it has been well demonstrated that the T. cruzi trans-sialidase affects the T cell intrathymic development resulting in an increase in the number of CD4⁺8⁺ double-positive recent thymic emigrants to the secondary lymphoid tissues. In the periphery, the coexpression of CD4 and CD8 molecules on the DP T cells released from the thymus may increase the affinity of the TCR during priming and so may reduce the threshold for costimulatory signals at T cell-dendritic cell immunological synapses [24, 25]. Since the DP T cells express TCR complex with CD4 and CD8 molecules, they would be able to recognize both peptide-class I and II MHC receptors at the same time, and these cells could rapidly eliminate APCs before other single-positive T cells could even be activated [26, 27]. Thus the DP T cells might have an immunodominant effect that could increase adaptive immune responses. The prematurely released activated DP thymocyte cells might also mature into functionally competent SP cells able to recognize pathogen antigens. Alternatively, they could express forbidden α βTCR with self-antigen specificities and could thus induce autoimmune responses.