Helios marks strongly autoreactive CD4+ T cells in two major waves of thymic deletion distinguished by induction of PD-1 or NF-κB

Abstract

Expression of the transcription factor Helios identifies thymocyte divergence during positive and negative selection.

Distinct phases in the positive selection of CD8+T cells distinguished by intrathymic migration and T-cell receptor signaling patterns

“…The switch in expression of CCR7 and CXCR4 can be detected on a substantial proportion of MHC class I-selected, but not MHC class II-selected DP thymocytes (15)(16)(17). Therefore, the timing of the switch in chemokine responsiveness and migration to the medulla appears to differ during CD4 versus CD8 T-cell development.…”

“…Mature SP thymocytes remain in the thymus for 4-5 d (33) and thus may accumulate to outnumber the MHC class I-selected DP thymocytes in the steady-state thymus. Moreover, analysis of steady-state MHC class II-restricted thymocytes suggests that the switch in chemokine-receptor expression occurs during the early CD4 SP stage rather than at the DP stage (15)(16)(17). Therefore, it seems likely that steady-state medullary thymocytes consist primarily of CD4 and CD8 SP thymocytes, along with DP thymocytes bearing class I MHC-restricted TCR.…”

“…Although more rapid migration and briefer signaling events during these later stages may provide some protection from negative selection, it is likely that there is still a substantial loss of thymocytes at this stage. Indeed, recent studies have shown that a substantial proportion of cell loss in the thymus results from negative selection, rather than death by neglect (16,43), and that the loss due to negative selection is particularly pronounced for the CD8 T-cell lineage (45). In addition, some thymocytes with moderate affinity for self may escape negative selection and give rise to peripheral T cells with the potential to respond to self (46).…”

“…Conversely, mature SP thymocytes express CCR7 and have diminished expression of CXCR4 (12)(13)(14). For MHC class IIrestricted selection, chemokine-receptor changes appear to occur early during the SP stage whereas thymocytes undergoing positive selection via MHC class I up-regulate CCR7 at the DP stage (15)(16)(17). However, it is unclear whether the switch in chemokinereceptor expression and migration to the medulla occurs after positive selection is complete, or whether positive selection continues after thymocytes migrate to the medulla.…”

Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma

“…The PD-1 pathway is critical for both positive and negative selection of T cells in the thymus and is necessary for development of systemic selftolerance. [33][34][35][36] As such, previous PD-1 blockade could have longlasting effects on the thymus, resulting in altered PD-1 expression and imbalanced processing of the large number of T cells infused during HSCT. In addition, PD-1 blockade may alter posttransplant immune reconstitution through its effects on circulating cytokines and antigenpresenting cells.…”