Search

CD4+CD25+Foxp3+ regulatory T (Treg) cells are generated during thymocyte development and play a crucial role in preventing the immune system from attacking the body's cells and tissues. However, how the formation of these cells is directed by T-cell receptor (TCR) recognition of self-peptide:major histocompatibility complex (MHC) ligands remains poorly understood. We show that an agonist self-peptide with which a TCR is strongly reactive can induce a combination of thymocyte deletion and CD4+CD25+Foxp3+ Treg cell formation in vivo. A weakly cross-reactive partial agonist self-peptide could similarly induce thymocyte deletion, but failed to induce Treg cell formation. These studies indicate that CD4+CD25+Foxp3+ Treg cell formation can require highly stringent recognition of an agonist self-peptide by developing thymocytes. They also refine the "avidity" model of thymocyte selection by demonstrating that the quality of the signal mediated by agonist self-peptides, rather than the overall intensity of TCR signaling, can be a critical factor in directing autoreactive thymocytes to undergo CD4+CD25+Foxp3+ Treg cell formation and/or deletion during their development. [ABSTRACT FROM AUTHOR]

Global efforts to end the tuberculosis (TB) epidemic by 2030 (SDG3.3) through improved TB case detection and treatment have not been effective to significantly reduce the global burden of the TB epidemic. This study presents an analytical framework to evaluate the use of TB case notification rates (CNR) to monitor and to evaluate TB under-detection and under-diagnoses in Bangladesh. Local indicators of spatial autocorrelation (LISA) were calculated to assess the presence and scale of spatial clusters of TB CNR across 489 upazilas in Bangladesh. Simultaneous autoregressive models were fit to the data to identify associations between TB CNR and poverty, TB testing rates and retreatment rates. CNRs were found to be significantly spatially clustered, negatively correlated to poverty rates and positively associated to TB testing and retreatment rates. Comparing the observed pattern of CNR with model-standardized rates made it possible to identify areas where TB under-detection is likely to occur. These results suggest that TB CNR is an unreliable proxy for TB incidence. Spatial variations in TB case notifications and subnational variations in TB case detection should be considered when monitoring national TB trends. These results provide useful information to target and prioritize context specific interventions. [ABSTRACT FROM AUTHOR]

CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells are generated during thymocyte development and play a crucial role in preventing the immune system from attacking the body's cells and tissues. However, how the formation of these cells is directed by T-cell receptor (TCR) recognition of self-peptide:major histocompatibility complex (MHC) ligands remains poorly understood. We show that an agonist self-peptide with which a TCR is strongly reactive can induce a combination of thymocyte deletion and CD4(+)CD25(+)Foxp3(+) Treg cell formation in vivo. A weakly cross-reactive partial agonist self-peptide could similarly induce thymocyte deletion, but failed to induce Treg cell formation. These studies indicate that CD4(+)CD25(+)Foxp3(+) Treg cell formation can require highly stringent recognition of an agonist self-peptide by developing thymocytes. They also refine the "avidity" model of thymocyte selection by demonstrating that the quality of the signal mediated by agonist self-peptides, rather than the overall intensity of TCR signaling, can be a critical factor in directing autoreactive thymocytes to undergo CD4(+)CD25(+)Foxp3(+) Treg cell formation and/or deletion during their development.